Novel glp-1 receptor modulators

ABSTRACT

The invention relates to compounds that modulate the glucagon-like peptide 1 (GLP-1) receptor, methods of their synthesis, and methods of their therapeutic and/or prophylactic use. Such compounds are act as modulators or potentiators of GLP-1 receptor on their own, or with receptor ligands including GLP-1 peptides GLP-1(7-36) and GLP-1(9-36), or with peptide-based therapies, such as exenatide and liraglutide, and have the following general structure (where “ ” represents either or both the R and S form of the compound): 
     
       
         
         
             
             
         
       
     
     where A, B, C, Y 1 , Y 2 , Z, R 1 , R 2 , R 3 , R 4 , R 5 , W 1 , n, p and q are as defined herein.

FIELD OF THE INVENTION

The invention relates to compounds that bind the glucagon-like peptide 1(GLP-1) receptor, methods of their synthesis, and methods of theirtherapeutic and/or prophylactic use. The present invention is directedto compounds adapted to act as modulators or potentiators of GLP-1receptor, including peptides GLP-1(7-36) and GLP-1(9-36), as well aspeptide-based therapies such as exenatide and liraglutide.

BACKGROUND

Glucagon-like peptide 1 receptor (GLP-1R) belongs to Family B1 of theseven-transmembrane G protein-coupled receptors, and its natural agonistligand is the peptide hormone glucagon-like peptide-1 (GLP-1). GLP-1 isa peptide hormone arising by its alternative enzymatic cleavage fromproglucagon, the prohormone precursor for GLP-1, which is highlyexpressed in enteroendocrine cells of the intestine, the alpha cells ofthe endocrine pancreas (islets of Langerhans), and the brain (Kieffer T.J. and Habener, J. F. Endocrin. Rev. 20:876-913 (1999); Drucker, D. J.,Endocrinology 142:521-7 (2001); Holst, J. J., Diabetes Metab. Res. Rev.18:430-41 (2002)). The initial actions of GLP-1 observed were on theinsulin-producing cells of the islets, where it stimulatesglucose-dependent insulin secretion. Subsequently, multiple additionalantidiabetogenic actions of GLP-1 were discovered including thestimulation of the growth and inhibition of the apoptosis of pancreaticbeta cells (Drucker, D. J., Endocrinology 144:5145-8 (2003); Holz, G. G.and Chepurny O. G., Curr. Med. Chem. 10:2471-83 (2003); List, J. F. andHabener, J. F., Am. J. Physiol. Endocrinol. Metab. 286:E875-81 (2004)).

On activation, GLP-1 receptors couple to the α-subunit of G protein,with subsequent activation of adenylate cyclase and increase of cAMPlevels, thereby potentiating glucose-stimulated insulin secretion.Therefore, GLP-1 is an attractive therapeutic target to lower bloodglucose and preserve the β-cells of the pancreas of diabetic patients.Glucagon has been used for decades in medical practice within diabetesand several glucagon-like peptides are being developed for varioustherapeutic indications. GLP-1 analogs and derivatives are beingdeveloped for the treatment for patients suffering from diabetes.

SUMMARY OF THE INVENTION

The present invention is directed to compounds adapted to act aspotentiators or modulators of GLP-1 receptor; methods of theirpreparation and methods of their use, such as in treatment of amalcondition mediated by GLP-1 receptor activation, or when modulationor potentiation of GLP-1 receptor is medically indicated.

Certain embodiments of the present invention comprise a compound havingthe structure of Formula I-R or I-S or a pharmaceutically acceptableisomer, enantiomer, racemate, salt, isotope, prodrug, hydrate or solvatethereof:

wherein

-   -   A is a 5-, 6- or 7-membered heterocyclyl having one, two or        three heteroatoms where each such heteroatom is independently        selected from O, N, and S, and where any ring atom of such        heterocyclyl may be optionally substituted with one or more of        R₄;    -   B is aryl, aralkyl, heterocyclyl, or heterocyclylalkyl;    -   C is aryl, arylalkyl, heterocyclyl or heterocyclylalkyl;    -   Y₁ and Y₂ are both null, or one of Y₁ or Y₂ is —NH— or —O— and        the other Y₁ or Y₂ is null;    -   Z is —C(O)— or —S(O)₂—;    -   each R₁ is independently H or C₁₋₄ alkyl;    -   R₂ is —OH, —O—R₈, —N(R₁)—SO₂—R₈, —NR₄₁R₄₂,        —N(R₁)—(CR_(a)R_(b))_(m)—COOH,        —N(R₁)—(CR_(a)R_(b))_(m)—CO—N(R₁)-heterocyclyl,        —N(R₁)—(CR_(a)R_(b))_(m)—CO—N(R₁)(R₇), or —N(R₁)-heterocyclyl;    -   each R₃ and R₄ is independently H, halo, alkyl, alkyl        substituted with R₃₁, alkoxy, haloalkyl, perhaloalkyl,        haloalkoxy, perhaloalkoxy, aryl, heterocyclyl, —OH, —OR₈, —CN,        —NO₂, —NR₁R₈, —C(O)R₈, —C(O)NR₁R₈, —NR₁C(O)R₈, —SR₈, —S(O)R₈,        —S(O)₂R₈, —OS(O)₂R₈, —S(O)₂NR₁R₈, —NR₁S(O)₂R₈,        —(CR_(a)R_(b))_(m)NR₁R₈, —(CR_(a)R_(b))_(m)O(CR_(a)R_(b))_(m)R₈,        —(CR_(a)R_(b))_(m)NR₁(CR_(a)R_(b))_(m)R₈ or        —(CR_(a)R_(b))_(m)NR₁(CR_(a)R_(b))_(m)COOH; or any two R₃ or R₄        groups on the same carbon atom taken together form oxo;    -   each R₃₁ is independently H, halo, hydroxyl, —NR₄₁R₄₂, or        alkoxy;    -   each R₄₀ is independently H or alkyl;    -   each R₄₁ and R₄₂ is independently R₄₀ or —(CH₂)_(n)—COO—R₄₀,        —C(O)—R₄₀, aryl, heteroaryl, or two taken together with the N        atom to which they are attached can form a 3- to 7-membered        heterocyclyl;    -   W₁ is null or -L₁-(CR_(a)R_(b))_(m)-L₁-R₆;    -   each L₁ is independently, from the proximal to distal end of the        structure of Formula I-R or I-S, null, —C(O)O—, —S(O₂)—, —S—,        —N(R₁)—C(O)—N(R₁)—, —N(R₁)—C(O)—O—, —C(O)— or —S(O₂)—NR₁—;    -   each R_(a) and R_(b) is independently H, alkyl, alkoxy, aryl,        arylalkyl, heterocyclyl or heterocyclylalkyl, any of which        alkyl, alkoxy, aryl, arylalkyl, heterocyclyl or        heterocyclylalkyl may be optionally (singly or multiply)        substituted with R₇, or —(CH₂)_(m)C(O)OR₄₀, —(CH₂)_(m)OR₄₀,        —(CH₂)_(m)SR₄₀, —(CH₂)_(m)NR₄₁R₄₂, —(CH₂)_(m)C(O)NR₄₁R₄₂; or any        two R_(a) and R_(b) taken together with the carbon to which they        are attached form a cycloalkyl or heterocyclyl; or R₁ and any        one of R_(a) or R_(b) taken together form heterocyclyl;    -   R₅ is R₇, —(CH₂)_(m)-L₂-(CH₂)_(m)—R₇, or        -(-L₂-(CR_(a)R_(b))_(r)-)_(s)-L₃-R₇;    -   R₆ is H, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl,        heterocycloalkyl, any of which may be optionally singly or        multiply substituted with R₇ or —(CH₂)_(m)-L₂-(CH₂)_(m)—R₇;    -   R₇ is H, halo, alkyl, haloalkyl, perhaloalkyl, alkoxy, —OH,        —OR₈, —CN, —NR₁R₈, —(CR_(a)R_(b))_(m)O(CR_(a)R_(b))_(m)R₈,        —NR₁(CR_(a)R_(b))_(m)R₈, —C(O)R₈, —NR₁(CR_(a)R_(b))_(m)COOH,        —NR₁C(O)R₈, —C(O)NR₁R₈, —SR₈, —S(O)R₈, —S(O)₂R₈, —S(O)₂NR₁R₈,        —NR₁S(O)₂R₈; or a ring moiety selected from cycloalkyl, aryl,        arylalkyl, heterocyclyl or heterocyclylalkyl, where such ring        moiety is optionally singly or multiply substituted with halo,        —OH, —CN, alkyl, alkoxy, haloalkyl or perhaloalkyl;        -   each R₈ is independently H, alkyl, cycloalkyl or aryl;        -   L₂ is independently, from the proximal to distal end of the            structure of Formula I-R or I-S, null, —O—, —OC(O)—, —NR₁—,            —C(O)NR₁—, —N(R₁)—C(O)—, —S(O₂)—, —C(O)— or —S(O₂)—N(R₁)—;        -   each L₃ is independently null, —O—, or —N(R₁)—        -   each m is independently 0, 1, 2, 3, 4, 5 or 6;        -   each n is independently 0 or 1 or 2;        -   p is 0, 1, 2 or 3;        -   q is 0, 1, 2 or 3;        -   each r is independently 2, 3, or 4; and        -   each s is independently 1, 2, 3, or 4.

In certain embodiments, a pharmaceutical composition comprising acompound of the invention together with at least one pharmaceuticallyacceptable carrier, diluent or excipient is provided.

In certain embodiments, a method of use of a compound of the inventioncomprising preparation of a medicament is provided.

In certain embodiments, the invention provides a pharmaceuticalcombination comprising a compound of the invention and a secondmedicament. In various such embodiments, the second medicament is anagonist or modulator for glucagon receptor, GIP receptor, GLP-2receptor, or PTH receptor, or glucagon-like peptide 1 (GLP-1) receptor.In various such embodiments, the second medicament is exenatide,liraglutide, taspoglutide, albiglutide, or lixisenatide or other insulinregulating peptide. In various such embodiments, the second medicamentis a DPPIV inhibitor. In various such embodiments, the second medicamentis medically indicated for the treatment of type II diabetes.

In certain embodiments, a method of activation, potentiation or agonismof a GLP-1 receptor is provided comprising contacting the receptor witha compound, pharmaceutical composition or pharmaceutical combination ofthe invention.

In certain embodiments, a method is provided for treatment of amalcondition in a subject for which activation, potentiation or agonismof a GLP-1 receptor is medically indicated where such method comprisesadministering to such subject a compound, pharmaceutical composition orpharmaceutical combination of the invention. In various suchembodiments, selective activation, potentiation or agonism of a GLP-1receptor, is medically indicated. In various such embodiments, themalcondition comprises type I diabetes, type II diabetes, gestationaldiabetes, obesity, excessive appetite, insufficient satiety, ormetabolic disorder.

In certain embodiments, the invention provides methods for synthesis ofcertain compounds including compounds of the invention. In certain otherembodiments, the invention provides certain intermediate compoundsassociated with such methods of synthesis.

DETAILED DESCRIPTION OF THE INVENTION

Certain embodiments comprise a compound having the chiral structure ofFormula I-R or I-S (with the chirality as indicated) or apharmaceutically acceptable isomer, enantiomer, racemate, salt, isotope,prodrug, hydrate or solvate thereof:

Certain embodiments of the present invention comprise a compound havingthe structure of Formula I-R or I-S or a pharmaceutically acceptableisomer, enantiomer, racemate, salt, isotope, prodrug, hydrate or solvatethereof:

where A, B, C, Y₁, Y₂, Z, R₁, R₂, R₃, R₄, R₅, W₁, n, p and q are asdefined above. In certain embodiments, the compounds have the structureof Formula I-R or a pharmaceutically acceptable isomer, enantiomer,salt, isotope, prodrug, hydrate or solvate thereof. In otherembodiments, the compounds have the structure of Formula I-S or apharmaceutically acceptable isomer, enantiomer, salt, isotope, prodrug,hydrate or solvate thereof.

In certain embodiments, the compounds can be substantiallyenantiomerically pure.

In certain embodiments, the invention provides a compound of Formula I-Rand/or Formula I-S where Y₁ and Y₂ are null, Z is —C(O)— and A is a 5-or 6-membered heteroaryl group. Representative compounds of thisembodiment include compounds of the following structures (wherein “

” represents either or both the R and S form of the compound):

In certain embodiments, the invention provides a compound where Y₁ andY₂ are null, Z is —C(O)— and A is a 5-, 6- or 7-membered non-aromaticheterocyclyl group. Representative compounds of this embodiment includecompounds of the following structures (wherein “

” represents either or both the R and S form of the compound):

In certain embodiments, the inventions provides compounds of each ofstructures I-R/S(1)-(29) where R₄ of the phenyl group is H.

In certain embodiments, the inventions provides compounds of each ofstructures I-R/S(1)-(29) where the A group (i.e., the 5-, 6- or7-membered heterocyclyl) is not substituted by R₄, or substituted by R₄where R₄ is alkyl, haloalkyl, alkoxy, —NR₄₁R₄₂ where R₄₁ and R₄₂ areindependently hydrogen or alkyl, or substituted by two R₄ groups whichtaken together form oxo.

In certain embodiments, the invention provides a compound of Formula I-Rand/or Formula I-S where Y₁ and Y₂ are null, Z is —C(O)— and A is C isaryl. Representative compounds of this embodiment include compounds ofthe following structures (wherein “

” represents either or both the R and S form of the compound):

In certain embodiments, the inventions provides compounds of each ofstructures I-R/S(30)-(32) where q is zero.

In certain embodiments, the inventions provides compounds of each ofstructures I-R/S(30)-(32) where q is one, two or three.

In certain embodiments, the inventions provides compounds of structureI-R/S(30) where q is one and R₅ is —(CH₂)_(m)-L₂-(CH₂)_(m)—R₇ or-(-L₃-(CR_(a)R_(b))_(r)-)_(s)-L₃-R₇. Representative compounds of thisembodiment include compounds of the following structure (wherein “

” represents either or both the R and S form of the compound):

In certain embodiments, the inventions provides compounds of structureI-R/S(33) where R₇ is H or alklyl and L₂ is O. Representative compoundsof this embodiment include compounds of the following structure (wherein“

” represents either or both the R and S form of the compound):

In certain embodiments, the inventions provides compounds of structureI-R/S(30) where R₅ is R₇. Representative compounds of this embodimentinclude compounds of the following structure (wherein “

” represents either or both the R and S form of the compound):

In certain embodiments, the invention provides compounds of structureI-R/S(35) where R₇ is halo, alkyl, haloalkyl, perhaloalkyl, alkoxy, —OH,—OR₈, —CN, —NR₁R₈, —(CR_(a)R_(b))_(m)O(CR_(a)R_(b))_(m)R₈,—NR₁(CR_(a)R_(b))_(m)R₈, —C(O)R₈, —NR₁(CR_(a)R_(b))_(m)COOH, —NR₁C(O)R₈,—C(O)NR₁R₈, —SR₈, —S(O)R₈, —S(O)₂R₈, —S(O)₂NR₁R₈ or —NR₁S(O)₂R₈.

In certain embodiments, the invention provides compounds of structureI-R/S(35) where R₇ is a ring moiety selected from cycloalkyl, aryl,arylalkyl, heterocyclyl or heterocyclylalkyl, where such ring moiety isoptionally (singly or multiply) substituted with halo, —OH, —CN, alkyl,alkoxy, haloalkyl or perhaloalkyl.

In certain embodiments, the invention provides a compound of Formula I-Rand/or Formula I-S where Y₁ and Y₂ are null, Z is —C(O)— and A is C isheterocyclyl. Representative compounds of this embodiment includecompounds of the following structures (wherein “

” represents either or both the R and S form of the compound):

In certain embodiments, the invention provides compounds of each ofstructures I-R/S(36)-(44) where R₇ is halo, alkyl, haloalkyl,perhaloalkyl, alkoxy, —OH, —OR₈, —CN, —NR₁R₈,—(CR_(a)R_(b))_(m)O(CR_(a)R_(b))_(m)R₈, —NR₁(CR_(a)R_(b))_(m)R₈,—C(O)R₈, —NR₁(CR_(a)R_(b))_(m)COOH, —NR₁C(O)R₈, —C(O)NR₁R₈, —SR₈,—S(O)R₈, —S(O)₂R₈, —S(O)₂NR₁R₈ or —NR₁S(O)₂R₈.

In certain embodiments, the invention provides compounds of each ofstructures I-R/S(36)-(44) where R₇ is a ring moiety selected fromcycloalkyl, aryl, arylalkyl, heterocyclyl or heterocyclylalkyl, wheresuch ring moiety is optionally (singly or multiply) substituted withhalo, —OH, —CN, alkyl, alkoxy, haloalkyl or perhaloalkyl.

In certain embodiments, the invention provides a compound of Formula I-Rand/or Formula I-S where Y₁ and Y₂ are null, Z is —C(O)— and B is arylor arylalkyl. Representative compounds of this embodiment includecompounds of the following structures (wherein “

” represents either or both the R and S form of the compound):

In certain embodiments, the invention provides compounds of each ofstructures I-R/S(45)-(48) where W₁ is null.

Representative compounds of this embodiment include compounds of thefollowing structure (wherein “

” represents either or both the R and S form of the compound):

In certain embodiments, the invention provides compounds of structureI-R/S(49) where R₃ is halo, alkyl, alkoxy, haloalkyl, perhaloalkyl,haloalkoxy, perhaloalkoxy, —OH, —OR₈, —CN, —NR₁R₈, —C(O)R₈, —C(O)NR₁R₈,—NR₁C(O)R₈, —SR₈, —S(O)R₈, —S(O)₂R₈, —OS(O)₂R₈, —S(O)₂NR₁R₈,—NR₁S(O)₂R₈, —(CR_(a)R_(b))_(m)NR₁R₈ or—(CR_(a)R_(b))_(m)O(CR_(a)R_(b))_(m)R₈.

In certain embodiments, the invention provides compounds of each ofstructures I-R/S(45)-(49) where R₃ is alkyl.

In certain embodiments, the invention provides a compound of Formula I-Rand/or Formula I-S where Y₁ and Y₂ are null, Z is —C(O)— and B isheterocyclyl or heterocyclylalkyl. Representative compounds of thisembodiment include compounds of the following structures (wherein “

” represents either or both the R and S form of the compound):

In certain embodiments, the invention provides compounds of each ofstructures I-R/S(50)-(62) where W₁ is null.

In certain embodiments, the invention provides compounds of each ofstructures I-R/S(50)-(62) where W₁ is null and R₃ is halo, alkyl,alkoxy, haloalkyl, perhaloalkyl, haloalkoxy, perhaloalkoxy, —OH, —OR₈,—CN, —NR₁R₈, —C(O)R₈, —C(O)NR₁R₈, —NR₁C(O)R₈, —SR₈, —S(O)R₈, —S(O)₂R₈,—OS(O)₂R₈, —S(O)₂NR₁R₈, —NR₁S(O)₂R₈, —(CR_(a)R_(b))_(m)NR₁R₈ or—(CR_(a)R_(b))_(m)O(CR_(a)R_(b))_(m)R₈.

In certain embodiments, the invention provides compounds of each ofstructures I-R/S(50)-(62) where W₁ is null, p is 1 and R₃ is alkyl.

In certain embodiments, the invention provides compounds of each ofstructures I-R/S(1)-(62) where R₂ is —OH, —N(R₁)—(CR_(a)R_(b))_(m)—COOHor —N(R₁)—SO₂—R₈; where R₁ is H; where R_(a) and R_(b) are independentlyH, alkyl, alkoxy, —(CH₂)_(m)C(O)NR₄₁R₄₂, —(CH₂)_(m)C(O)OR₄₀,—(CH₂)_(m)NR₄₁R₄₂, —(CH₂)_(m)SR₄₀, —N(R₁)-heterocyclyl, aryl optionallysubstituted with R₇, or wherein R₁ and any one of R_(a) or R_(b) takentogether form heterocyclyl; R₈ is alkyl; and m is 1 or 2.

In certain embodiments, the invention provides compounds of thefollowing structures (wherein “

” represents either or both the R and S form of the compound):

In certain embodiments, the invention provides compounds of structureI-R/S(63) where A is a 5-membered heteroaryl.

In certain embodiments, the invention provides compounds of structureI-R/S(63) where A is a 6-membered heteroaryl.

In certain embodiments, the invention provides compounds of structureI-R/S(63) where A is a 6-membered heteroaryl having one or two nitrogenatoms.

In certain embodiments, the invention provides compounds of structureI-R/S(63) where A is pyrimindinyl.

In certain embodiments, the invention provides compounds of structureI-R/S(63) where A is pyridinyl.

In certain embodiments, the invention provides compounds of structureI-R/S(63) where B is aryl.

In certain embodiments, the invention provides compounds of structureI-R/S(63) where B is phenyl.

In certain embodiments, the invention provides compounds of structureI-R/S(63) where B is heteroaryl.

In certain embodiments, the invention provides compounds of structureI-R/S(63) where B is thiophenyl.

In certain embodiments, the invention provides compounds of structureI-R/S(63) where R₂ is —OH.

In certain embodiments, the invention provides compounds of structureI-R/S(63) where R₂ is —NH(CR_(a)R_(b))_(m)COOH.

In certain embodiments, the invention provides compounds of structureI-R/S(63) where R₂ is —NHSO₂R₈.

In certain embodiments, the invention provides compounds of structureI-R/S(63) where R₂ is —NHCH₂COOH.

In certain embodiments, the invention provides compounds of structureI-R/S(63) where R₂ is —NH(CHR_(b))COOH where R_(b) is alkyl,—(CH₂)_(m)OR₄₀, —(CH₂)_(m)SR₄₀, —(CH₂)_(m)C(O)OR₄₀, —(CH₂)_(m)NR₄₁R₄₂ or—(CH₂)_(m)C(O)NR₄₁R₄₂.

In certain embodiments, the invention provides compounds of structureI-R/S(63) where R₂ is —NH(CR_(a)R_(b))_(m)COOH where R_(a) and R_(b) areindependently H, alkyl, —(CH₂)_(m)OR₄₀, —(CH₂)_(m)SR₄₀,—(CH₂)_(m)C(O)OR₄₀, —(CH₂)_(m)NR₄₁R₄₂ or —(CH₂)_(m)C(O)NR₄₁R₄₂.

In certain embodiments, the invention provides compounds of structureI-R/S(63) where R₂ is —NR₁(CHR_(b))COOH where R₁ and R_(b) takentogether form heterocyclyl.

In certain embodiments, the invention provides compounds of structureI-R/S(63) where R₂ is —NR₁(CR_(a)R_(b))_(m)COOH where R₁ and one ofR_(b) taken together form heterocyclyl.

In certain embodiments, the invention provides compounds of structureI-R/S(63) where any two R_(a) and R_(b) taken together with the carbonto which they are attached form a cycloalkyl.

In certain embodiments, the invention provides compounds of structureI-R/S(63) where R₂ is —NH(CR_(a)R_(b))_(m)COOH where one of R_(a) andR_(b) is H and the other R_(a) and R_(b) is aryl substituted with R₇.

In certain embodiments, the invention provides compounds of structureI-R/S(63) where p is 1 or 2 and each R₃ is independently alkyl, alkoxy,—OH, perhaloalkyl or —C(O)R₈.

In certain embodiments, the invention provides compounds of structureI-R/S(63) where p is 1 and each R₃ is alkyl.

In certain embodiments, the invention provides compounds of structureI-R/S(63) where q is 1 and R₅ is —(CH₂)_(m)-L₂-(CH₂)_(m)—R₇.

In certain embodiments, the invention provides compounds of structureI-R/S(63) where q is 1 and R₅ is alkoxy.

In certain embodiments, the invention provides a compound of Formula I-Rand/or Formula I-S where Y₁ and Y₂ are null and Z is —S(O)₂—.Representative compounds of this embodiment include compounds of thefollowing structures (wherein “

” represents either or both the R and S form of the compound):

In certain embodiments, the invention provides compounds of structureI-R/S(64) where A is pyrimidinyl, B is phenyl and C is phenyl.Representative compounds of this embodiment include compounds of thefollowing structure (wherein “

” represents either or both the R and S form of the compound):

In certain embodiments, the invention provides a compound of Formula I-Rand/or Formula I-S where Y₁ is null, Y₂ is —O— and Z is —C(O)—.Representative compounds of this embodiment include compounds of thefollowing structures (wherein “

” represents either or both the R and S form of the compound):

In certain embodiments, the invention provides a compound of Formula I-Rand/or Formula I-S where Y₁ is NH, Y₂ is null and Z is —C(O)—.Representative compounds of this embodiment include compounds of thefollowing structures (wherein “

” represents either or both the R and S form of the compound):

In certain embodiments, the invention provides a pharmaceuticalcomposition comprising a compound of the invention together with atleast one pharmaceutically acceptable carrier, diluent or excipient.

In certain embodiments, the invention provides a pharmaceuticalcomposition comprising a compound of the invention and a secondmedicament. In certain of such embodiments, the second medicament is aGLP-1 agonist or a DPPIV inhibitor.

In certain embodiments, the invention provides a method of use ofcompounds of the invention for preparation of a medicament.

In certain embodiments, the invention provides a pharmaceuticalcombination comprising a compound of the invention and a secondmedicament. In various such embodiments, the second medicament is anagonist or modulator for glucagon receptor, GIP receptor, GLP-2receptor, or PTH receptor, or glucagon-like peptide 1 (GLP-1) receptor.In various such embodiments, the second medicament is exenatide,liraglutide, taspoglutide, albiglutide, or lixisenatide or other insulinregulating peptide. In various such embodiments, the second medicamentis a DPPIV inhibitor. In various such embodiments, the second medicamentis medically indicated for the treatment of type II diabetes.

In certain embodiments, a method is provided for activation,potentiation or agonism of a glucagon-like peptide 1 comprisingcontacting the receptor with an effective amount of a compound,pharmaceutical composition or pharmaceutical combination of theinvention.

In further embodiments, a method is provided for activation or agonismof a GLP-1 receptor by contacting the receptor with an effective amountof an invention compound and GLP-1 peptides GLP-1 (9-36) and GLP-1(7-36), pharmaceutical composition or pharmaceutical combination,wherein the GLP-1 receptor is disposed within a living mammal; incertain embodiments wherein such mammal is a human.

In certain embodiments, a method is provided for treatment of amalcondition in a subject for which activation, potentiation or agonismof a GLP-1 receptor is medically indicated, by administering aneffective amount of an invention compound to the subject at a frequencyand for a duration of time sufficient to provide a beneficial effect tothe patient. In yet further embodiments, a method is provided fortreatment of a malcondition in a patient for which activation,potentiation, or agonism of a GLP-1 receptor is medically indicated, byadministering an effective amount of an invention compound to thepatient at a frequency and for a duration of time sufficient to providea beneficial effect to the patient, wherein the malcondition comprisestype I diabetes, type II diabetes, gestational diabetes, obesity,excessive appetite, insufficient satiety, or metabolic disorder. Incertain embodiments, the subject is a patient or a human being. Incertain embodiments, the human being is afflicted with, or at risk ofdeveloping, a disease or condition selected from the group consisting oftype I diabetes, type II diabetes, gestational diabetes, obesity,excessive appetite, insufficient satiety, and metabolic disorder. Incertain of such embodiments, said disease is type I diabetes or type IIdiabetes.

In certain embodiments, the invention provides methods for synthesis ofcertain compounds including compounds of the invention as more fullyillustrated herein. In certain other embodiments, the invention providescertain intermediate compounds associated with such methods of synthesisas illustrated herein.

In certain embodiments, methods are provided for use of an inventioncompound for preparation of a medicament adapted for treatment of adisorder or a malcondition wherein activation or inhibition of a GLP-1receptor is medically indicated. In certain embodiments, themalcondition comprises type I diabetes, type II diabetes, gestationaldiabetes, obesity, excessive appetite, insufficient satiety, andmetabolic disorder. Preferably said disease is type I diabetes or typeII diabetes.

In certain embodiments, the method additionally comprises administeringto the subject a second medicament selected from the group of peptidicGLP-1 agonists and DPPIV inhibitors, wherein such second medicament iseither a component of the pharmaceutical composition or a secondpharmaceutical composition. In certain of such embodiments, the secondmedicament can be exenatide or sitagliptin.

As used in the specification and the appended claims, the singular forms“a,” “an” and “the” include plural referents unless the context clearlydictates otherwise.

As used herein, “individual” (as in the subject of the treatment) meansboth mammals and non-mammals. Mammals include, for example, humans;non-human primates, e.g., apes and monkeys; cattle; horses; sheep; andgoats. Non-mammals include, for example, fish and birds.

A “receptor”, as is well known in the art, is a biomolecular entityusually comprising a protein that specifically binds a structural classof ligands or a single native ligand in a living organism, the bindingof which causes the receptor to transduce the binding signal intoanother kind of biological action, such as signaling a cell that abinding event has occurred, which causes the cell to alter its functionin some manner. An example of transduction is receptor binding of aligand causing alteration of the activity of a “G-protein” in thecytoplasm of a living cell. Any molecule, naturally occurring or not,that binds to a receptor and activates it for signal transduction, isreferred to as an “agonist” or “activator.” Any molecule, naturallyoccurring or not, that binds to a receptor, but does not cause signaltransduction to occur, and which can block the binding of an agonist andits consequent signal transduction, is referred to as an “antagonist.”Certain molecules bind to receptors at locations other than the bindingsites of their natural ligands and such allosteric binding molecules maypotentiate, activate or agonize the receptor and may enhance the effectof a natural ligand or a co-administered ligand.

An “GLP-1 compound” or “GLP-1 agonist” or “GLP-1 activator” or “GLP-1inhibitor” or “GLP-1 antagonist” or “GLP-1 potentiator” or “GLP-1modulator” as the terms are used herein refer to compounds that interactin some way with the GLP-1 receptor. They can be agonists, potentiators,or activators, or they can be antagonists or inhibitors. An “GLP-1compound” of the invention can be selective for action of the GLP-1receptor family.

“Substantially” as the term is used herein means completely or almostcompletely; for example, a composition that is “substantially free” of acomponent either has none of the component or contains such a traceamount that any relevant functional property of the composition isunaffected by the presence of the trace amount, or a compound is“substantially pure” is there are only negligible traces of impuritiespresent.

Substantially enantiomerically or diasteromerically pure means a levelof enantiomeric or diasteromeric enrichment of one enantiomer withrespect to the other enantiomer or diasteromer of at least 90%, 95%,98%, 99%, 99.5% or 99.9%.

“Treating” or “treatment” within the meaning herein refers to analleviation of symptoms associated with a disorder or disease, orinhibition of further progression or worsening of those symptoms, orprevention or prophylaxis of the disease or disorder.

The expression “effective amount”, when used to describe use of acompound of the invention in providing therapy to a patient sufferingfrom a disorder or malcondition mediated by GLP-1 refers to the amountof a compound of the invention that is effective to bind to as anagonist or as an antagonist a GLP-1 receptor in the individual'stissues, wherein the GLP-1 is implicated in the disorder, wherein suchbinding occurs to an extent sufficient to produce a beneficialtherapeutic effect on the patient. Similarly, as used herein, an“effective amount” or a “therapeutically effective amount” of a compoundof the invention refers to an amount of the compound that alleviates, inwhole or in part, symptoms associated with the disorder or condition, orhalts or slows further progression or worsening of those symptoms, orprevents or provides prophylaxis for the disorder or condition. Inparticular, a “therapeutically effective amount” refers to an amounteffective, at dosages and for periods of time necessary, to achieve thedesired therapeutic result by acting as an agonist of GLP-1 activity. Atherapeutically effective amount is also one in which any toxic ordetrimental effects of compounds of the invention are outweighed by thetherapeutically beneficial effects. For example, in the context oftreating a malcondition mediated by activation of a GLP-1 receptor, atherapeutically effective amount of a GLP-1 receptor agonist of theinvention is an amount sufficient to control the malcondition, tomitigate the progress of the malcondition, or to relieve the symptoms ofthe malcondition. Examples of malconditions that can be so treatedinclude, but not limited to, type II diabetes.

All chiral, diastereomeric, racemic forms of a structure are intended,unless a particular stereochemistry or isomeric form is specificallyindicated. Compounds used in the present invention can include enrichedor resolved optical isomers at any or all asymmetric atoms as areapparent from the depictions, at any degree of enrichment. Both racemicand diastereomeric mixtures, as well as the individual optical isomerscan be synthesized so as to be substantially free of their enantiomericor diastereomeric partners, and these are all within the scope ofcertain embodiments of the invention.

The isomers resulting from the presence of a chiral center comprise apair of non-superimposable isomers that are called “enantiomers.” Singleenantiomers of a pure compound are optically active, i.e., they arecapable of rotating the plane of plane polarized light. Singleenantiomers are designated according to the Cahn-Ingold-Prelog system.Once the priority ranking of the four groups is determined, the moleculeis oriented so that the lowest ranking group is pointed away from theviewer. Then, if the descending rank order of the other groups proceedsclockwise, the molecule is designated (R) and if the descending rank ofthe other groups proceeds counterclockwise, the molecule is designated(S). In the example in Scheme 14, the Cahn-Ingold-Prelog ranking isA>B>C>D. The lowest ranking atom, D is oriented away from the viewer.

“Isolated optical isomer” means a compound which has been substantiallypurified from the corresponding optical isomer(s) of the same formula.Preferably, the isolated isomer is at least about 80%, more preferablyat least 90% pure, even more preferably at least 98% pure, mostpreferably at least about 99% pure, by weight.

Enantiomers are sometimes called optical isomers because a pureenantiomer rotates plane-polarized light in a particular direction. Ifthe light rotates clockwise, then that enantiomer is labeled “(+)” or“d” for dextrorotatory, its counterpart will rotate the lightcounterclockwise and is labeled “(−)” or “1” for levorotatory.

The terms “racemate” and “racemic mixture” are frequently usedinterchangeably. A racemate is an equal mixture of two enantiomers. Aracemate is labeled “(±)” because it is not optically active (i.e., willnot rotate plane-polarized light in either direction since itsconstituent enantiomers cancel each other out).

It is understood that due to chemical properties (i.e., resonancelending some double bond character to the C—N bond) of restrictedrotation about the amide bond linkage (as illustrated below) it ispossible to observe separate rotamer species and even, under somecircumstances, to isolate such species, example shown below. It isfurther understood that certain structural elements, including stericbulk or substituents on the amide nitrogen, may enhance the stability ofa rotamer to the extent that a compound may be isolated as, and existindefinitely, as a single stable rotamer. The present inventiontherefore includes any possible stable rotamers of compounds of theinvention which are biologically active in the treatment of type Idiabetes, type II diabetes, gestational diabetes, obesity, excessiveappetite, insufficient satiety, or metabolic disorder.

The preferred compounds of the present invention have a particularspatial arrangement of substituents on the aromatic rings, which isrelated to the structure activity relationship demonstrated by thecompound class. Often such substitution arrangement is denoted by anumbering system; however, numbering systems are often not consistentbetween different ring systems. In six-membered aromatic systems, thespatial arrangements are specified by the common nomenclature “para” for1,4-substitution, “meta” for 1,3-substitution and “ortho” for1,2-substitution as shown below.

All structures encompassed within a claim are “chemically feasible”, bywhich is meant that the structure depicted by any combination orsubcombination of optional substituents meant to be recited by the claimis physically capable of existence with at least some stability as canbe determined by the laws of structural chemistry and byexperimentation. Structures that are not chemically feasible are notwithin a claimed set of compounds. Further, isotopes of the atomsdepicted (such as deuterium and tritium in the case of hydrogen) areencompassed within the scope of this invention.

In general, “substituted” refers to an organic group as defined hereinin which one or more bonds to a hydrogen atom contained therein arereplaced by one or more bonds to a non-hydrogen atom such as, but notlimited to, a halogen (i.e., F, Cl, Br, and I); an oxygen atom in groupssuch as hydroxyl groups, alkoxy groups, aryloxy groups, aralkyloxygroups, oxo(carbonyl) groups, carboxyl groups including carboxylicacids, carboxylates, and carboyxlate esters; a sulfur atom in groupssuch as thiol groups, alkyl and aryl sulfide groups, sulfoxide groups,sulfone groups, sulfonyl groups, and sulfonamide groups; a nitrogen atomin groups such as amines, hydroxylamines, nitriles, nitro groups,N-oxides, hydrazides, azides, and enamines; and other heteroatoms invarious other groups. Non-limiting examples of substituents that can bebonded to a substituted carbon (or other) atom include F, Cl, Br, I,OR′, OC(O)N(R′)₂, CN, CF₃, OCF₃, R′, O, S, C(O), S(O), methylenedioxy,ethylenedioxy, N(R′)₂, SR′, SOR′, SO₂R′, SO₂N(R)₂, SO₃R′, C(O)R′,C(O)C(O)R′, C(O)CH₂C(O)R′, C(S)R′, C(O)OR′, OC(O)R′, C(O)N(R′)₂,OC(O)N(R′)₂, C(S)N(R′)₂, (CH₂)₀₋₂NHC(O)R′, (CH₂)₀₋₂N(R′)N(R′)₂,N(R′)N(R′)C(O)R′, N(R′)N(R′)C(O)OR′, N(R′)N(R′)CON(R′)₂, N(R′)SO₂R′,N(R)SO₂N(R′)₂, N(R′)C(O)OR′, N(R′)C(O)R′, N(R′)C(S)R′, N(R′)C(O)N(R′)₂,N(R′)C(S)N(R′)₂, N(COR′)COR′, N(OR′)R′, C(═NH)N(R′)₂, C(O)N(OR′)R′, orC(═NOR′)R′ wherein R′ can be hydrogen or a carbon-based moiety, andwherein the carbon-based moiety can itself be further substituted.

Substituted alkyl, alkenyl, alkynyl, cycloalkyl, and cycloalkenyl groupsas well as other substituted groups also include groups in which one ormore bonds to a hydrogen atom are replaced by one or more bonds,including double or triple bonds, to a carbon atom, or to a heteroatomsuch as, but not limited to, oxygen in carbonyl (oxo), carboxyl, ester,amide, imide, urethane, and urea groups; and nitrogen in imines,hydroxyimines, oximes, hydrazones, amidines, guanidines, and nitriles.

Substituted ring groups includes substituted aryl, heterocyclyl andheteroaryl groups. Substituted ring groups can be substituted by one ormore substituents at any available ring position. In some embodiments,two substituents on a substituted ring group may taken together with thering to which they are attached to form a ring, such that the two ringsare fused together. For example, benzodioxolyl is a fused ring systemformed by two substituents taken together on a phenyl group.

Such substituted ring groups also include rings and fused ring systemsin which a bond to a hydrogen atom is replaced with a bond to a carbonatom. Therefore, substituted aryl, heterocyclyl and heteroaryl groupscan also be substituted with alkyl, alkenyl, cycloalkyl, aryl,heteroaryl, and alkynyl groups as defined herein, which can themselvesbe further substituted.

The linking groups (e.g., L₁ and L₂) of Formula I-R or I-S are partialstructures which may be represented by a formula, say, for example,—N(R₁)—C(O)—, which is read from left-to-right. Accordingly, thenitrogen atom of the —N(R₁)—C(O)— linker will be attached to theproximal end of the structure of Formula I-R or I-S, and the carbonylcarbon atom of the —N(R₁)—C(O)— linker will be attached to the distalend of the structure of Formula I-R or I-S.

The term “heteroatoms” as used herein refers to non-carbon andnon-hydrogen atoms, capable of forming covalent bonds with carbon, andis not otherwise limited. Typical heteroatoms are N, O, and S. Whensulfur (S) is referred to, it is understood that the sulfur can be inany of the oxidation states in which it is found, thus includingsulfoxides (R—S(O)—R′) and sulfones (R—S(O)₂—R′), unless the oxidationstate is specified; thus, the term “sulfone” encompasses only thesulfone form of sulfur; the term “sulfide” encompasses only the sulfide(R—S—R′) form of sulfur. When the phrases such as “heteroatoms selectedfrom the group consisting of O, NH, NR′ and S,” or “[variable] is O, S .. . ” are used, they are understood to encompass all of the sulfide,sulfoxide and sulfone oxidation states of sulfur.

Alkyl groups include straight chain and branched alkyl groups andcycloalkyl groups having from 1 to about 20 carbon atoms, and typicallyfrom 1 to 12 carbons (C₁-C₁₂ alkyl), or, in some embodiments, from 1 to8 carbon atoms (C₁-C₈ alkyl), or, in some embodiments, from 1 to 4carbon atoms (C₁-C₄ alkyl). Examples of straight chain alkyl groupsinclude, but are not limited to, methyl, ethyl, n-propyl, n-butyl,n-pentyl, n-hexyl, n-heptyl, and n-octyl groups. Examples of branchedalkyl groups include, but are not limited to, isopropyl, iso-butyl,sec-butyl, t-butyl, neopentyl, isopentyl, and 2,2-dimethylpropyl groups.Alkyl groups as used herein may optionally include one or more furthersubstituent groups. Representative substituted alkyl groups can besubstituted one or more times with any of the groups listed above, forexample, amino, hydroxy, cyano, carboxy, nitro, thio, alkoxy, andhalogen groups.

Cycloalkyl groups are alkyl groups forming a ring structure, which canbe substituted or unsubstituted, wherein the ring is either completelysaturated, partially unsaturated, or fully unsaturated, wherein if thereis unsaturation, the conjugation of the pi-electrons in the ring do notgive rise to aromaticity. Examples of cycloalkyl include, but are notlimited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, and cyclooctyl groups. In some embodiments, the cycloalkylgroup has 3 to 8 ring members, whereas in other embodiments the numberof ring carbon atoms range from 3 to 5, 3 to 6, or 3 to 7. Cycloalkylgroups further include polycyclic cycloalkyl groups such as, but notlimited to, norbornyl, adamantyl, bornyl, camphenyl, isocamphenyl, andcarenyl groups, and fused rings such as, but not limited to, decalinyl,and the like. Cycloalkyl groups also include rings that are substitutedwith straight or branched chain alkyl groups as defined above.Representative substituted cycloalkyl groups can be mono-substituted orsubstituted one or more times with any of the groups listed above, forexample, but not limited to, amino, hydroxy, cyano, carboxy, nitro,thio, alkoxy, and halogen groups.

The terms “carbocyclic” and “carbocycle” denote a ring structure whereinthe atoms of the ring are carbon. In some embodiments, the carbocyclehas 3 to 8 ring members, whereas in other embodiments the number of ringcarbon atoms is 4, 5, 6, or 7. Unless specifically indicated to thecontrary, the carbocyclic ring can be substituted with as many as Nsubstituents wherein N is the size of the carbocyclic ring with forexample, amino, hydroxy, cyano, carboxy, nitro, thio, alkoxy, andhalogen groups.

(Cycloalkyl)alkyl groups, also denoted cycloalkylalkyl, are alkyl groupsas defined above in which a hydrogen or carbon bond of the alkyl groupis replaced with a bond to a cycloalkyl group as defined above.

Alkenyl groups include straight and branched chain and cyclic alkylgroups as defined above, except that at least one double bond existsbetween two carbon atoms. Thus, alkenyl groups have from 2 to about 20carbon atoms, and typically from 2 to 12 carbons or, in someembodiments, from 2 to 8 carbon atoms. Examples include, but are notlimited to —CH═CH(CH₃), —CH═C(CH₃)₂, —C(CH₃)═CH₂, —C(CH₃)═CH(CH₃),—C(CH₂CH₃)═CH₂, vinyl, cyclohexenyl, cyclopentenyl, cyclohexadienyl,butadienyl, pentadienyl, and hexadienyl among others.

The term “cycloalkenyl” alone or in combination denotes a cyclic alkenylgroup wherein at least one double bond is present in the ring structure.Cycloalkenyl groups include cycloalkyl groups having at least one doublebond between two adjacent carbon atoms. Thus for example, cycloalkenylgroups include but are not limited to cyclohexenyl, cyclopentenyl, andcyclohexadienyl groups.

(Cycloalkenyl)alkyl groups are alkyl groups as defined above in which ahydrogen or carbon bond of the alkyl group is replaced with a bond to acycloalkenyl group as defined above.

Alkynyl groups include straight and branched chain alkyl groups, exceptthat at least one triple bond exists between two carbon atoms. Thus,alkynyl groups have from 2 to about 20 carbon atoms, and typically from2 to 12 carbons or, in some embodiments, from 2 to 8 carbon atoms.Examples include, but are not limited to —C≡CH, —C≡C(CH₃), —C≡C(CH₂CH₃),—CH₂C≡CH, —CH₂C≡C(CH₃), and —CH₂C≡C(CH₂CH₃), among others.

Aryl groups are cyclic aromatic hydrocarbons that do not containheteroatoms. Thus aryl groups include, but are not limited to, phenyl,azulenyl, heptalenyl, biphenyl, indacenyl, fluorenyl, phenanthrenyl,triphenylenyl, pyrenyl, naphthacenyl, chrysenyl, biphenylenyl,anthracenyl, and naphthyl groups. In some embodiments, aryl groupscontain 6-14 carbons in the ring portions of the groups. The phrase“aryl groups” includes groups containing fused rings, such as fusedaromatic-aliphatic ring systems (e.g., indanyl, tetrahydronaphthyl, andthe like), and also includes substituted aryl groups that have othergroups, including but not limited to alkyl, halo, amino, hydroxy, cyano,carboxy, nitro, thio, or alkoxy groups, bonded to one of the ring atoms.Representative substituted aryl groups can be mono-substituted orsubstituted more than once, such as, but not limited to, 2-, 3-, 4-, 5-,or 6-substituted phenyl or naphthyl groups, which can be substitutedwith groups including but not limited to those listed above.

Aralkyl groups are alkyl groups as defined above in which a hydrogenatom of an alkyl group is replaced with an aryl group as defined above.Representative aralkyl groups include benzyl and phenylethyl groups andfused (cycloalkylaryl)alkyl groups such as 4-ethyl-indanyl. The arylmoiety or the alkyl moiety or both are optionally substituted with othergroups, including but not limited to alkyl, halo, amino, hydroxy, cyano,carboxy, nitro, thio, or alkoxy groups. Aralkenyl group are alkenylgroups as defined above in which a hydrogen or carbon bond of an alkylgroup is replaced with a bond to an aryl group as defined above.

Heterocyclyl or heterocyclic groups include aromatic and non-aromaticring moieties containing 3 or more ring members, of which one or more isa heteroatom such as, but not limited to, N, O, S, or P. In someembodiments, heterocyclyl groups include 3 to 20 ring members, whereasother such groups have 3 to 15 ring members, including for examplesingle ring systems containing 5, 6 or 7 ring members. At least one ringcontains a heteroatom, but every ring in a polycyclic system need notcontain a heteroatom. For example, a dioxolanyl ring and abenzdioxolanyl ring system (methylenedioxyphenyl ring system) are bothheterocyclyl groups within the meaning herein. A heterocyclyl groupdesignated as a C₂-heterocyclyl can be a 5-ring with two carbon atomsand three heteroatoms, a 6-ring with two carbon atoms and fourheteroatoms, and so forth. Likewise a C₄-heterocyclyl can be a 5-ringwith one heteroatom, a 6-ring with two heteroatoms, and so forth. Thenumber of carbon atoms plus the number of heteroatoms sums up to equalthe total number of ring atoms.

The term “heterocyclyl” includes fused ring species including thosehaving fused aromatic and non-aromatic groups. The phrase also includespolycyclic ring systems containing a heteroatom such as, but not limitedto, quinuclidyl and also includes heterocyclyl groups that havesubstituents, including but not limited to alkyl, halo, amino, hydroxy,cyano, carboxy, nitro, thio, or alkoxy groups, bonded to one of the ringmembers. A heterocyclyl group as defined herein can be a heteroarylgroup or a partially or completely saturated cyclic group including atleast one ring heteroatom. Heterocyclyl groups include, but are notlimited to, pyrazinyl, pyrimidinyl, pyridazinyl, thiadiazolyl,oxadiazolyl, imidazolinyl, hexahydropyrimidinyl, diazepanyl, triazinyl,imidazolyl, pyrrolidinyl, furanyl, tetrahydrofuranyl,tetrahydro-2H-pyranyl, dioxolanyl, piperidinyl, piperazinyl,morpholinyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl,isoxazolyl, thiazolyl, pyridinyl, thiophenyl, benzothiophenyl,benzofuranyl, dihydrobenzofuranyl, indolyl, dihydroindolyl, azaindolyl,indazolyl, benzimidazolyl, azabenzimidazolyl, benzoxazolyl,benzothiazolyl, benzothiadiazolyl, imidazopyridinyl, isoxazolopyridinyl,thianaphthalenyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl,isoquinolinyl, tetrahydroquinolinyl, quinoxalinyl, and quinazolinylgroups. Heterocyclyl groups can be substituted. Representativesubstituted heterocyclyl groups can be mono-substituted or substitutedmore than once, including but not limited to, rings containing at leastone heteroatom which are mono, di, tri, tetra, penta, hexa, orhigher-substituted with substituents such as those listed above,including but not limited to alkyl, halo, amino, hydroxy, cyano,carboxy, nitro, thio, and alkoxy groups.

Heteroaryl groups are aromatic ring moieties containing 5 or more ringmembers, of which, one or more is a heteroatom such as, but not limitedto, N, O, and S. A heteroaryl group designated as a C₂₋heteroaryl can bea 5-ring with two carbon atoms and three heteroatoms, a 6-ring with twocarbon atoms and four heteroatoms and so forth. Likewise a C₄-heteroarylcan be a 5-ring with one heteroatom, a 6-ring with two heteroatoms, andso forth. The number of carbon atoms plus the number of heteroatoms sumsup to equal the total number of ring atoms. Heteroaryl groups include,but are not limited to, groups such as pyrrolyl, pyrazolyl, pyridinyl,pyridazinyl, pyrimidyl, pyrazyl, pyrazinyl, pyrimidinyl, thiadiazolyl,imidazolyl, oxadiazolyl, thienyl, triazolyl, tetrazolyl, triazinyl,thiazolyl, thiophenyl, oxazolyl, isoxazolyl, benzothiophenyl,benzofuranyl, indolyl, azaindolyl, indazolyl, benzimidazolyl,azabenzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl,imidazopyridinyl, isoxazolopyridinyl, thianaphthalenyl, purinyl,xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl,tetrahydroquinolinyl, tetrahydroisoquinolinyl, quinoxalinyl, andquinazolinyl groups. The terms “heteroaryl” and “heteroaryl groups”include fused ring compounds such as wherein at least one ring, but notnecessarily all rings, are aromatic, including tetrahydroquinolinyl,tetrahydroisoquinolinyl, indolyl and 2,3-dihydro indolyl. The term alsoincludes heteroaryl groups that have other groups bonded to one of thering members, including but not limited to alkyl, halo, amino, hydroxy,cyano, carboxy, nitro, thio, or alkoxy groups. Representativesubstituted heteroaryl groups can be substituted one or more times withgroups such as those listed above.

Additional examples of aryl and heteroaryl groups include but are notlimited to phenyl, biphenyl, indenyl, naphthyl (1-naphthyl, 2-naphthyl),N-hydroxytetrazolyl, N-hydroxytriazolyl, N-hydroxyimidazolyl,anthracenyl (1-anthracenyl, 2-anthracenyl, 3-anthracenyl), thiophenyl(2-thienyl, 3-thienyl), furyl (2-furyl, 3-furyl), indolyl, oxadiazolyl(1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl), thiadiazolyl(1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl), isoxazolyl, quinazolinyl,fluorenyl, xanthenyl, isoindanyl, benzhydryl, acridinyl, thiazolyl,pyrrolyl (2-pyrrolyl), pyrazolyl (3-pyrazolyl), imidazolyl(1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), triazolyl(1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl 1,2,3-triazol-4-yl,1,2,4-triazol-3-yl), oxazolyl (2-oxazolyl, 4-oxazolyl, 5-oxazolyl),thiazolyl (2-thiazolyl, 4-thiazolyl, 5-thiazolyl), pyridyl (2-pyridyl,3-pyridyl, 4-pyridyl), pyrimidinyl (2-pyrimidinyl, 4-pyrimidinyl,5-pyrimidinyl, 6-pyrimidinyl), pyrazinyl, pyridazinyl (3-pyridazinyl,4-pyridazinyl, 5-pyridazinyl), pyrazolo[1,5-c]pyridinyl, quinolyl(2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 6-quinolyl, 7-quinolyl,8-quinolyl), isoquinolyl (1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl,5-isoquinolyl, 6-isoquinolyl, 7-isoquinolyl, 8-isoquinolyl),benzo[b]furanyl (2-benzo[b]furanyl, 3-benzo[b]furanyl,4-benzo[b]furanyl, 5-benzo[b]furanyl, 6-benzo[b]furanyl,7-benzo[b]furanyl), isobenzofuranyl, 2,3-dihydro-benzo[b]furanyl(2-(2,3-dihydro-benzo[b]furanyl), 3-(2,3-dihydro-benzo[b]furanyl),4-(2,3-dihydro-benzo[b]furanyl), 5-(2,3-dihydro-benzo[b]furanyl),6-(2,3-dihydro-benzo[b]furanyl), 7-(2,3-dihydro-benzo[b]furanyl),benzo[b]thiophenyl (2-benzo[b]thiophenyl, 3-benzo[b]thiophenyl,4-benzo[b]thiophenyl, 5-benzo[b]thiophenyl, 6-benzo[b]thiophenyl,7-benzo[b]thiophenyl), 2,3-dihydro-benzo[b]thiophenyl,(2-(2,3-dihydro-benzo[b]thiophenyl), 3-(2,3-dihydro-benzo[b]thiophenyl),4-(2,3-dihydro-benzo[b]thiophenyl), 5-(2,3-dihydro-benzo[b]thiophenyl),6-(2,3-dihydro-benzo[b]thiophenyl), 7-(2,3-dihydro-benzo[b]thiophenyl),indolyl (1-indolyl, 2-indolyl, 3-indolyl, 4-indolyl, 5-indolyl,6-indolyl, 7-indolyl), indazole (1-indazolyl, 3-indazolyl, 4-indazolyl,5-indazolyl, 6-indazolyl, 7-indazolyl), benzimidazolyl(1-benzimidazolyl, 2-benzimidazolyl, 4-benzimidazolyl, 5-benzimidazolyl,6-benzimidazolyl, 7-benzimidazolyl, 8-benzimidazolyl), benzoxazolyl(1-benzoxazolyl, 2-benzoxazolyl), benzothiazolyl (1-benzothiazolyl,2-benzothiazolyl, 4-benzothiazolyl, 5-benzothiazolyl, 6-benzothiazolyl,7-benzothiazolyl), benzo[d]isoxazolyl, carbazolyl (1-carbazolyl,2-carbazolyl, 3-carbazolyl, 4-carbazolyl), 5H-dibenz[b,f]azepine(5H-dibenz[b,f]azepin-1-yl, 5H-dibenz[b,f]azepine-2-yl,5H-dibenz[b,f]azepine-3-yl, 5H-dibenz[b,f]azepine-4-yl,5H-dibenz[b,f]azepine-5-yl), 10,11-dihydro-5H-dibenz[b,f]azepine(10,11-dihydro-5H-dibenz[b,f]azepine-1-yl,10,11-dihydro-5H-dibenz[b,f]azepine-2-yl,10,11-dihydro-5H-dibenz[b,f]azepine-3-yl,10,11-dihydro-5H-dibenz[b,f]azepine-4-yl,10,11-dihydro-5H-dibenz[b,f]azepine-5-yl), and the like.

Heterocyclylalkyl groups are alkyl groups as defined above in which ahydrogen or carbon bond of an alkyl group is replaced with a bond to aheterocyclyl group as defined above. Representative heterocyclyl alkylgroups include, but are not limited to, furan-2-yl methyl, furan-3-ylmethyl, pyridine-2-yl methyl (α-picolyl), pyridine-3-yl methyl(β-picolyl), pyridine-4-yl methyl (γ-picolyl), tetrahydrofuran-2-ylethyl, and indol-2-yl propyl. Heterocyclylalkyl groups can besubstituted on the heterocyclyl moiety, the alkyl moiety, or both.

Heteroarylalkyl groups are alkyl groups as defined above in which ahydrogen or carbon bond of an alkyl group is replaced with a bond to aheteroaryl group as defined above. Heteroarylalkyl groups can besubstituted on the heteroaryl moiety, the alkyl moiety, or both.

By a “ring system” as the term is used herein is meant a moietycomprising one, two, three or more rings, which can be substituted withnon-ring groups or with other ring systems, or both, which can be fullysaturated, partially unsaturated, fully unsaturated, or aromatic, andwhen the ring system includes more than a single ring, the rings can befused, bridging, or spirocyclic. By “spirocyclic” is meant the class ofstructures wherein two rings are fused at a single tetrahedral carbonatom, as is well known in the art.

A “monocyclic, bicyclic or polycyclic, aromatic or partially aromaticring” as the term is used herein refers to a ring system including anunsaturated ring possessing 4n+2 pi electrons, or a partially reduced(hydrogenated) form thereof. The aromatic or partially aromatic ring caninclude additional fused, bridged, or spiro rings that are notthemselves aromatic or partially aromatic. For example, naphthalene andtetrahydronaphthalene are both a “monocyclic, bicyclic or polycyclic,aromatic or partially aromatic ring” within the meaning herein. Also,for example, a benzo-[2.2.2]-bicyclooctane is also a “monocyclic,bicyclic or polycyclic, aromatic or partially aromatic ring” within themeaning herein, containing a phenyl ring fused to a bridged bicyclicsystem. A fully saturated ring has no double bonds therein, and iscarbocyclic or heterocyclic depending on the presence of heteroatomswithin the meaning herein.

When two “R” groups are said to be joined together or taken together toform a ring, it is meant that together with the carbon atom or anon-carbon atom (e.g., nitrogen atom), to which they are bonded, theymay form a ring system. In general, they are bonded to one another toform a 3- to 7-membered ring, or a 5- to 7-membered ring. Non-limitingspecific examples are the cyclopentyl, cyclohexyl, cycloheptyl,piperidinyl, piperazinyl, pyrrolidinyl, pyrrolyl, pyridinyl.

The term “alkoxy” refers to an oxygen atom connected to an alkyl group,including a cycloalkyl group, as are defined above. Examples of linearalkoxy groups include but are not limited to methoxy, ethoxy, n-propoxy,n-butoxy, n-pentyloxy, n-hexyloxy, n-heptyloxy, n-octyloxy n-nonyloxy,and the like. Examples of branched alkoxy include but are not limited toisopropoxy, sec-butoxy, tert-butoxy, isopentyloxy, isohexyloxy, and thelike. Examples of cyclic alkoxy include but are not limited tocyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and thelike.

The terms “aryloxy” and “arylalkoxy” refer to, respectively, an arylgroup bonded to an oxygen atom and an aralkyl group bonded to the oxygenatom at the alkyl moiety. Examples include but are not limited tophenoxy, naphthyloxy, and benzyloxy.

An “acyl” group as the term is used herein refers to a group containinga carbonyl moiety wherein the group is bonded via the carbonyl carbonatom. The carbonyl carbon atom is also bonded to another carbon atom,which can be part of an alkyl, aryl, aralkyl cycloalkyl,cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl,heteroarylalkyl group or the like. In the special case wherein thecarbonyl carbon atom is bonded to a hydrogen, the group is a “formyl”group, an acyl group as the term is defined herein. An acyl group caninclude 0 to about 12-20 additional carbon atoms bonded to the carbonylgroup. An acyl group can include double or triple bonds within themeaning herein. An acryloyl group is an example of an acyl group. Anacyl group can also include heteroatoms within the meaning here. Anicotinoyl group (pyridyl-3-carbonyl) group is an example of an acylgroup within the meaning herein. Other examples include acetyl, benzoyl,phenylacetyl, pyridylacetyl, cinnamoyl, and acryloyl groups and thelike. When the group containing the carbon atom that is bonded to thecarbonyl carbon atom contains a halogen, the group is termed a“haloacyl” group. An example is a trifluoroacetyl group.

The term “amine” includes primary, secondary, and tertiary amineshaving, e.g., the formula N(group)₃ wherein each group can independentlybe H or non-H, such as alkyl, aryl, and the like. Amines include but arenot limited to R—NH₂, for example, alkylamines, arylamines,alkylarylamines; R₂NH wherein each R is independently selected, such asdialkylamines, diarylamines, aralkylamines, heterocyclylamines and thelike; and R₃N wherein each R is independently selected, such astrialkylamines, dialkylarylamines, alkyldiarylamines, triarylamines, andthe like. The term “amine” also includes ammonium ions as used herein.

An “amino” group is a substituent of the form —NH₂, —NHR, —NR₂, —NR₃ ⁺,wherein each R is independently selected, and protonated forms of each.Accordingly, any compound substituted with an amino group can be viewedas an amine.

An “ammonium” ion includes the unsubstituted ammonium ion NH₄ ⁺, butunless otherwise specified, it also includes any protonated orquaternarized forms of amines. Thus, trimethylammonium hydrochloride andtetramethylammonium chloride are both ammonium ions, and amines, withinthe meaning herein.

The term “amide” (or “amido”) includes C- and N-amide groups, i.e.,—C(O)NR₂, and —NRC(O)R groups, respectively. Amide groups thereforeinclude but are not limited to carbamoyl groups (—C(O)NH₂) and formamidegroups (—NHC(O)H). A “carboxamido” group is a group of the formulaC(O)NR₂, wherein R can be H, alkyl, aryl, etc.

The term “carbonyl,” refers to a —C(O)— group.

“Halo,” “halogen,” and “halide” include fluorine, chlorine, bromine andiodine.

The term “perhaloalkyl” refers to an alkyl group where all of thehydrogen atoms are replaced by halogen atoms. Perhaloalkyl groupsinclude, but are not limited to, —CF₃ and —C(CF₃)₃. The term “haloalkyl”refers to an alkyl group where some but not necessarily all of thehydrogen atoms are replaced by halogen atoms. Haloalkyl groups includebut are not limited to —CHF₂ and —CH₂F.

The term “perhaloalkoxy” refers to an alkoxy group where all of thehydrogen atoms are replaced by halogen atoms. Perhaloalkoxy groupsinclude, but are not limited to, —OCF₃ and —OC(CF₃)₃. The term“haloalkoxy” refers to an alkoxy group where some but not necessarilyall of the hydrogen atoms are replaced by halogen atoms. Haloalkoxygroups include but are not limited to —OCHF₂ and —OCH₂F.

The terms “comprising,” “including,” “having,” “composed of,” areopen-ended terms as used herein, and do not preclude the existence ofadditional elements or components. In a claim element, use of the forms“comprising,” “including,” “having,” or “composed of” means thatwhatever element is comprised, had, included, or composes is notnecessarily the only element encompassed by the subject of the clausethat contains that word.

A “salt” as is well known in the art includes an organic compound suchas a carboxylic acid, a sulfonic acid, or an amine, in ionic form, incombination with a counterion. For example, acids in their anionic formcan form salts with cations such as metal cations, for example sodium,potassium, and the like; with ammonium salts such as NH₄ ⁺ or thecations of various amines, including tetraalkyl ammonium salts such astetramethylammonium, or other cations such as trimethylsulfonium, andthe like. A “pharmaceutically acceptable” or “pharmacologicallyacceptable” salt is a salt formed from an ion that has been approved forhuman consumption and is generally non-toxic, such as a chloride salt ora sodium salt. A “zwitterion” is an internal salt such as can be formedin a molecule that has at least two ionizable groups, one forming ananion and the other a cation, which serve to balance each other. Forexample, amino acids such as glycine can exist in a zwitterionic form. A“zwitterion” is a salt within the meaning herein. The compounds of thepresent invention may take the form of salts. The term “salts” embracesaddition salts of free acids or free bases which are compounds of theinvention. Salts can be “pharmaceutically-acceptable salts.” The term“pharmaceutically-acceptable salt” refers to salts which possesstoxicity profiles within a range that affords utility in pharmaceuticalapplications. Pharmaceutically unacceptable salts may nonethelesspossess properties such as high crystallinity, which have utility in thepractice of the present invention, such as for example utility inprocess of synthesis, purification or formulation of compounds of theinvention.

Suitable pharmaceutically-acceptable acid addition salts may be preparedfrom an inorganic acid or from an organic acid. Examples of inorganicacids include hydrochloric, hydrobromic, hydriodic, nitric, carbonic,sulfuric, and phosphoric acids. Appropriate organic acids may beselected from aliphatic, cycloaliphatic, aromatic, araliphatic,heterocyclic, carboxylic and sulfonic classes of organic acids, examplesof which include formic, acetic, propionic, succinic, glycolic,gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic,fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic,4-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic),methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic,trifluoromethanesulfonic, 2-hydroxyethanesulfonic, p-toluenesulfonic,sulfanilic, cyclohexylaminosulfonic, stearic, alginic, β-hydroxybutyric,salicylic, galactaric and galacturonic acid. Examples ofpharmaceutically unacceptable acid addition salts include, for example,perchlorates and tetrafluoroborates.

Suitable pharmaceutically acceptable base addition salts of compounds ofthe invention include, for example, metallic salts including alkalimetal, alkaline earth metal and transition metal salts such as, forexample, calcium, magnesium, potassium, sodium and zinc salts.Pharmaceutically acceptable base addition salts also include organicsalts made from basic amines such as, for example,N,N-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine,ethylenediamine, meglumine (N-methylglucamine) and procaine. Examples ofpharmaceutically unacceptable base addition salts include lithium saltsand cyanate salts. Although pharmaceutically unacceptable salts are notgenerally useful as medicaments, such salts may be useful, for exampleas intermediates in the synthesis of Formula I compounds, for example intheir purification by recrystallization. All of these salts may beprepared by conventional means from the corresponding compound accordingto Formula I by reacting, for example, the appropriate acid or base withthe compound according to Formula I. The term “pharmaceuticallyacceptable salts” refers to nontoxic inorganic or organic acid and/orbase addition salts, see, for example, Lit et al., Salt Selection forBasic Drugs (1986), Int J. Pharm., 33, 201-217, incorporated byreference herein.

A “hydrate” is a compound that exists in a composition with watermolecules. The composition can include water in stoichiometricquantities, such as a monohydrate or a dihydrate, or can include waterin random amounts. As the term is used herein a “hydrate” refers to asolid form, i.e., a compound in water solution, while it may behydrated, is not a hydrate as the term is used herein.

A “solvate” is a similar composition except that a solvent other thatwater replaces the water. For example, methanol or ethanol can form an“alcoholate”, which can again be stoichiometric or non-stoichiometric.As the term is used herein a “solvate” refers to a solid form, i.e., acompound in solution in a solvent, while it may be solvated, is not asolvate as the term is used herein.

A “prodrug” as is well known in the art is a substance that can beadministered to a patient where the substance is converted in vivo bythe action of biochemicals within the patient's body, such as enzymes,to the active pharmaceutical ingredient. Examples of prodrugs includeesters of carboxylic acid groups, which can be hydrolyzed by endogenousesterases as are found in the bloodstream of humans and other mammals.

“Isotopes” are well know in the art and refer to atoms with the samenumber of protons but different number of neutrons. For example, carbon12, the most common form of carbon, has six protons and six neutrons,whereas carbon 14 has six protons and eight neutrons.

In addition, where features or aspects of the invention are described interms of Markush groups, those skilled in the art will recognize thatthe invention is also thereby described in terms of any individualmember or subgroup of members of the Markush group. For example, if X isdescribed as selected from the group consisting of bromine, chlorine,and iodine, claims for X being bromine and claims for X being bromineand chlorine are fully described. Moreover, where features or aspects ofthe invention are described in terms of Markush groups, those skilled inthe art will recognize that the invention is also thereby described interms of any combination of individual members or subgroups of membersof Markush groups. Thus, for example, if X is described as selected fromthe group consisting of bromine, chlorine, and iodine, and Y isdescribed as selected from the group consisting of methyl, ethyl, andpropyl, claims for X being bromine and Y being methyl are fullydescribed.

Compositions and Combination Treatments

The GLP-1 compounds, their pharmaceutically acceptable salts orhydrolyzable esters of the present invention may be combined with apharmaceutically acceptable carrier to provide pharmaceuticalcompositions useful for treating the biological conditions or disordersnoted herein in mammalian species, and more preferably, in humans. Theparticular carrier employed in these pharmaceutical compositions mayvary depending upon the type of administration desired (e.g.,intravenous, oral, topical, suppository, or parenteral).

In preparing the compositions in oral liquid dosage forms (e.g.,suspensions, elixirs and solutions), typical pharmaceutical media, suchas water, glycols, oils, alcohols, flavoring agents, preservatives,coloring agents and the like can be employed. Similarly, when preparingoral solid dosage forms (e.g., powders, tablets and capsules), carrierssuch as starches, sugars, diluents, granulating agents, lubricants,binders, disintegrating agents and the like can be employed.

Another aspect of an embodiment of the invention provides compositionsof the compounds of the invention, alone or in combination with anotherGLP-1 agonist or another type of therapeutic agent, or both.Non-limiting examples of the GLP-1 receptor agonists include exenatide,liraglutide, taspoglutide, albiglutide, lixisenatide, and mixturesthereof.

In one embodiment, the GLP-1 agonist is exenatide (Byetta®) or ByettaLAR®. Exenatide is described, for example, in U.S. Pat. Nos. 5,424,286;6,902,744; 7,297,761, and others, the contents of each of which isherein incorporated by reference in its entirety.

In one embodiment, the GLP-1 agonist is liraglutide (VICTOZA®) (alsocalled NN-2211 and [Arg34,Lys26]-(N-epsilon-(gamma-Glu(N-alpha-hexadecanoyl))-GLP-1 (7-37)),includes the sequence HAEGTFTSDVSSYLEGQAAKEFIAWKVRGRG and is availablefrom Novo Nordisk (Denmark) or Scios (Fremont, Calif. USA). See, e.g.,Elbrond et al., 2002, Diabetes Care. August; 25(8):1398404; Agerso etal., 2002, Diabetologia. February; 45(2):195-202).

In one embodiment, the GLP-1 agonist is taspoglutide (CAS Registry No.275371-94-3) and is available from Hoffman La-Roche. See, for example,U.S. Pat. No. 7,368,427, the contents of which are herein incorporatedby reference in its entirety.

In one embodiment, the GLP-1 agonist is albiglutide (SYNCRIA® fromGlaxoSmithKline).

In another embodiment, the GLP-1 agonist is lixisenatide (Lyxumia® fromSanofi-Aventis/Zealand Pharma)

As set forth herein, compounds of the invention include stereoisomers,tautomers, solvates, hydrates, salts including pharmaceuticallyacceptable salts, and mixtures thereof. Compositions containing acompound of the invention can be prepared by conventional techniques,e.g., as described in Remington: The Science and Practice of Pharmacy,19th Ed., 1995, incorporated by reference herein. The compositions canappear in conventional forms, for example capsules, tablets, aerosols,solutions, suspensions or topical applications.

Typical compositions include a compound of the invention and apharmaceutically acceptable excipient which can be a carrier or adiluent. For example, the active compound will usually be mixed with acarrier, or diluted by a carrier, or enclosed within a carrier which canbe in the form of an ampoule, capsule, sachet, paper, or othercontainer. When the active compound is mixed with a carrier, or when thecarrier serves as a diluent, it can be solid, semi-solid, or liquidmaterial that acts as a vehicle, excipient, or medium for the activecompound. The active compound can be adsorbed on a granular solidcarrier, for example contained in a sachet. Some examples of suitablecarriers are water, salt solutions, alcohols, polyethylene glycols,polyhydroxyethoxylated castor oil, peanut oil, olive oil, gelatin,lactose, terra alba, sucrose, dextrin, magnesium carbonate, sugar,cyclodextrin, amylose, magnesium stearate, talc, gelatin, agar, pectin,acacia, stearic acid or lower alkyl ethers of cellulose, silicic acid,fatty acids, fatty acid amines, fatty acid monoglycerides anddiglycerides, pentaerythritol fatty acid esters, polyoxyethylene,hydroxymethylcellulose and polyvinylpyrrolidone. Similarly, the carrieror diluent can include any sustained release material known in the art,such as glyceryl monostearate or glyceryl distearate, alone or mixedwith a wax.

The formulations can be mixed with auxiliary agents which do notdeleteriously react with the active compounds. Such additives caninclude wetting agents, emulsifying and suspending agents, salt forinfluencing osmotic pressure, buffers and/or coloring substancespreserving agents, sweetening agents or flavoring agents. Thecompositions can also be sterilized if desired.

The route of administration can be any route which effectivelytransports the active compound of the invention to the appropriate ordesired site of action, such as oral, nasal, pulmonary, buccal,subdermal, intradermal, transdermal or parenteral, e.g., rectal, depot,subcutaneous, intravenous, intraurethral, intramuscular, intranasal,ophthalmic solution or an ointment, the oral route being preferred.

For parenteral administration, the carrier will typically comprisesterile water, although other ingredients that aid solubility or serveas preservatives can also be included. Furthermore, injectablesuspensions can also be prepared, in which case appropriate liquidcarriers, suspending agents and the like can be employed.

For topical administration, the compounds of the present invention canbe formulated using bland, moisturizing bases such as ointments orcreams.

If a solid carrier is used for oral administration, the preparation canbe tabletted, placed in a hard gelatin capsule in powder or pellet formor it can be in the form of a troche or lozenge. If a liquid carrier isused, the preparation can be in the form of a syrup, emulsion, softgelatin capsule or sterile injectable liquid such as an aqueous ornon-aqueous liquid suspension or solution.

Injectable dosage forms generally include aqueous suspensions or oilsuspensions which can be prepared using a suitable dispersant or wettingagent and a suspending agent Injectable forms can be in solution phaseor in the form of a suspension, which is prepared with a solvent ordiluent. Acceptable solvents or vehicles include sterilized water,Ringer's solution, or an isotonic aqueous saline solution.Alternatively, sterile oils can be employed as solvents or suspendingagents. Preferably, the oil or fatty acid is non-volatile, includingnatural or synthetic oils, fatty acids, mono-, di- or tri-glycerides.

For injection, the formulation can also be a powder suitable forreconstitution with an appropriate solution as described above. Examplesof these include, but are not limited to, freeze dried, rotary dried orspray dried powders, amorphous powders, granules, precipitates, orparticulates. For injection, the formulations can optionally containstabilizers, pH modifiers, surfactants, bioavailability modifiers andcombinations of these. The compounds can be formulated for parenteraladministration by injection such as by bolus injection or continuousinfusion. A unit dosage form for injection can be in ampoules or inmulti-dose containers.

The formulations of the invention can be designed to provide quick,sustained, or delayed release of the active ingredient afteradministration to the patient by employing procedures well known in theart. Thus, the formulations can also be formulated for controlledrelease or for slow release.

Compositions contemplated by the present invention can include, forexample, micelles or liposomes, or some other encapsulated form, or canbe administered in an extended release form to provide a prolongedstorage and/or delivery effect. Therefore, the formulations can becompressed into pellets or cylinders and implanted intramuscularly orsubcutaneously as depot injections. Such implants can employ known inertmaterials such as silicones and biodegradable polymers, e.g.,polylactide-polyglycolide. Examples of other biodegradable polymersinclude poly(orthoesters) and poly(anhydrides).

For nasal administration, the preparation can contain a compound of theinvention, dissolved or suspended in a liquid carrier, preferably anaqueous carrier, for aerosol application. The carrier can containadditives such as solubilizing agents, e.g., propylene glycol,surfactants, absorption enhancers such as lecithin (phosphatidylcholine)or cyclodextrin, or preservatives such as parabens.

For parenteral application, particularly suitable are injectablesolutions or suspensions, preferably aqueous solutions with the activecompound dissolved in polyhydroxylated castor oil.

Dosage forms can be administered daily, or more than once a day, such astwice or thrice daily. Alternatively dosage forms can be administeredless frequently than daily, such as every other day, or weekly, if foundto be advisable by a prescribing physician.

An embodiment of the invention also encompasses prodrugs of a compoundof the invention which on administration undergo chemical conversion bymetabolic or other physiological processes before becoming activepharmacological substances. Conversion by metabolic or otherphysiological processes includes without limitation enzymatic (e.g,specific enzymatically catalyzed) and non-enzymatic (e.g., general orspecific acid or base induced) chemical transformation of the prodruginto the active pharmacological substance. In general, such prodrugswill be functional derivatives of a compound of the invention which arereadily convertible in vivo into a compound of the invention.Conventional procedures for the selection and preparation of suitableprodrug derivatives are described, for example, in Design of Prodrugs,ed. H. Bundgaard, Elsevier, 1985.

In another embodiment, there are provided methods of making acomposition of a compound described herein including formulating acompound of the invention with a pharmaceutically acceptable carrier ordiluent. In some embodiments, the pharmaceutically acceptable carrier ordiluent is suitable for oral administration. In some such embodiments,the methods can further include the step of formulating the compositioninto a tablet or capsule. In other embodiments, the pharmaceuticallyacceptable carrier or diluent is suitable for parenteral administration.In some such embodiments, the methods further include the step oflyophilizing the composition to form a lyophilized preparation.

The compounds of the invention can be used therapeutically incombination with i) one or more other GLP-1 modulators and/or ii) one ormore other types of therapeutic agents which can be administered orallyin the same dosage form, in a separate oral dosage form (e.g.,sequentially or non-sequentially) or by injection together or separately(e.g., sequentially or non-sequentially). Examples of combinationtherapeutic agents include Sitagliptin (MK-0431, Januvia) an oralantihyperglycemic (antidiabetic drug) of the dipeptidyl peptidase-4(DPP-4) inhibitor class and Exenatide (Byetta) an incretin mimetic.

Combinations of the invention include mixtures of compounds from (a) and(b) in a single formulation and compounds from (a) and (b) as separateformulations. Some combinations of the invention can be packaged asseparate formulations in a kit. In some embodiments, two or morecompounds from (b) are formulated together while a compound of theinvention is formulated separately.

The dosages and formulations for the other agents to be employed, whereapplicable, will be as set out in the latest edition of the Physicians'Desk Reference, incorporated herein by reference.

Methods of Treatment

In certain embodiments, the present invention encompasses compounds thatbind with high affinity and specificity to the GLP-1 receptor in anagonist manner or as an activator or a potentiator. In certainembodiments a compound of the invention acts as a positive allostericmodulator of GLP-1 receptor.

In certain embodiments, the present invention provides a method foractivating, potentiating, or agonizing (i.e., to have an agonic effect,to act as an agonist) a GLP-1 receptor, with a compound of theinvention. The method involves contacting the receptor with a suitableconcentration of an inventive compound to bring about activation of thereceptor. The contacting can take place in vitro, for example incarrying out an assay to determine the GLP-1 receptor activationactivity of an inventive compound undergoing experimentation related toa submission for regulatory approval.

In certain embodiments, the method for activating an GLP-1 receptor, canalso be carried out in vivo, that is, within the living body of amammal, such as a human patient or a test animal. The inventive compoundcan be supplied to the living organism via one of the routes asdescribed above, e.g., orally, or can be provided locally within thebody tissues. In the presence of the inventive compound, activation ofthe receptor takes place, and the effect thereof can be studied.

An embodiment of the present invention provides a method of treatment ofa malcondition in a patient for which activation of an GLP-1 receptor ismedically indicated, wherein the patient is administered the inventivecompound in a dosage, at a frequency, and for a duration to produce abeneficial effect on the patient. The inventive compound can beadministered by any suitable means, examples of which are describedabove.

In certain embodiments, the present invention is directed to compoundsadapted to act as modulators or potentiators of Class B GPCRs. Thesecompounds may have activity on their own or in the presence of receptorligands. Receptors include incretin peptides including GLP-1 (7-36) andGLP-1 (9-36).

Methods of treatments provided by the invention include administrationof a compound of the invention, alone or in combination with anotherpharmacologically active agent to a subject or patient having amalcondition for which activation, potentiation or agonism of aglucagon-like peptide 1 receptor is medically indicated such as type Idiabetes, type II diabetes, gestational diabetes, obesity, excessiveappetite, insufficient satiety, or metabolic disorder.

PREPARATION OF CERTAIN EMBODIMENTS General Synthetic Methods forPreparing Compounds

Molecular embodiments of the present invention can be synthesized usingstandard synthetic techniques known to those of skill in the art.Compounds of the present invention can be synthesized using the generalsynthetic procedures set forth in Schemes 1-21.

-   -   Reagents: PG₁ and PG₂ are protecting groups: (i) If Z═CO then        Amide coupling with acid-Cl: DIEA, DCM or amide coupling with        acid: EDC, HOBt, DMF or HATU, DMF; If Z═SO₂, then coupling with        sulfonyl-chloride: DIEA or NEt₃, DCM or DMF; (ii) Deprotection        of PG₁ e.g., methyl ester deprotection: LiOH, dioxane, water.

The other enantiomer can be prepared in a similar manner using Scheme 1.

-   -   Reagents: (i) Zn(CN)₂, Pd(PPh₃)₄, NMP; (ii) NH₂OH HCl, TEA,        EtOH.

-   -   Reagents: PG is a protecting group (i) EDC, HOBt, DMF then        heat; (ii) Deprotection e.g., methyl ester deprotection: NaOH,        MeOH, water.

The other enantiomer can be prepared in a similar manner using Scheme 3.

-   -   Reagents: PG is a protecting group (i) NH₂OH, TEA, water or        EtOH; (ii) EDC, HOBt, DMF then heat; (iii) Deprotection e.g.,        methyl ester deprotection: NaOH, MeOH, water.

The other enantiomer can be prepared in a similar manner using Scheme 4.

-   -   Reagents: X₁═O or S; (i) N-Methylmorpholine, isobutyl        chloroformate, THF, DMF; (ii) For X₁=oxygen, then        2-Chloro-1,3-dimethylimidazolinium chloride, TEA, DCM; For        X₁=sulfur then        2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane        2,4-disulfide, THF; (iii) Deprotection e.g., methyl ester        deprotection: NaOH, MeOH, water.

The other enantiomer can be prepared in a similar manner using Scheme 5.

-   -   Reagents: PG is a protecting group (i) For Z═CO, then Amide        coupling with acid-Cl: DIEA, DCM or amide coupling with acid:        EDC, HOBt, DMF or HATU, DMF; For Z═SO₂, then coupling with        sulfonyl chloride DIEA or NEt₃, DCM or DMF (ii) DIEA,        1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide,        DCM; (iii) KOAc, bis-pinacolatoborane, PdCl₂(dppf) or        Pd(dppf)Cl₂, Na₂CO₃, THF, MeCN, water; (iv) Pd(dppf)Cl₂, Na₂CO₃,        THF, MeCN, water; (v) Pd(dppf)Cl₂, Na₂CO₃, THF, MeCN,        water; (vi) Deprotection e.g., methyl ester deprotection: NaOH,        MeOH, water. Each occurrence of X_(A) and X_(B) is independently        CR₄ or N.

The other enantiomer can be prepared in a similar manner using Scheme 6.

-   -   Reagents: PG is a protecting group; (i) Pd(dppf)Cl₂, Na₂CO₃,        THF, MeCN, water; (ii) Pd(dppf)Cl₂, Na₂CO₃, THF, MeCN,        water; (iii) Deprotection e.g., methyl ester deprotection: NaOH,        MeOH, water. Each occurrence of X_(A) and X_(B) is independently        CR₄ or N.

The other enantiomer can be prepared in a similar manner using Scheme 7.

-   -   Reagents: PG is a protecting group (i) DIEA or TEA,        acetonitrile; (ii) Acetamide, boron trifluoride etherate,        DCM; (iii) Deprotection e.g., methyl ester deprotection: NaOH,        MeOH, water.

The other enantiomer can be prepared in a similar manner using Scheme 8.

-   -   Reagents: PG is a protecting group (i) Boron trifluoride        etherate, acetamide, DCM; (ii) Zn, I₂, Pd₂(dba)₃,        dicyclohexyl(2′,6′-dimethoxy-[1,1′-biphenyl]-2-yl)phosphine,        DMF; (iii) Deprotection e.g., methyl ester deprotection: NaOH,        MeOH, water.

The other enantiomer can be prepared in a similar manner using Scheme 9.

-   -   Reagents: PG is a protecting group (i) Pd(dppf)Cl₂, Na₂CO₃, THF,        MeCN, water; (ii) Deprotection e.g., methyl ester deprotection:        NaOH, MeOH, water.

The other enantiomer can be prepared in a similar manner using Scheme10.

-   -   Reagents: PG is a protecting group (i) Pd(dppf)Cl₂, Na₂CO₃, THF,        MeCN, water; (ii) Deprotection e.g., tert-butyl ester        deprotection: DCM, TFA

The other enantiomer can be prepared in a similar manner using Scheme11.

-   -   Reagents: PG₁, PG₂, and PG₃ are protecting groups (i) Zn, I₂,        Pd₂(dba)₃,        dicyclohexyl(2′,6′-dimethoxy-[1,1′-biphenyl]-2-yl)phosphine,        DMF; (ii) Deprotection of PG₂ e.g., tert-butyl carbonate and        PG₃, e.g., SEM deprotection: DCM, TFA; (iii) If Z═CO then        coupling with acd: base (DIEA, TEA, or NMM), coupling reagents        (EDC, HOBt or DCC, HOBt, or DCC, DMAP or HATU), solvent (DMF or        DCM); If Z═SO₂ then coupling with sulfonyl-Cl: DIEA or TEA, DCM        or DMF; (iv) Deprotection of PG, e.g., tert-butyl ester        deprotection: DCM, TFA

The other enantiomer can be prepared in a similar manner using Scheme12.

-   -   Reagents: PG₁ and PG₂ are protecting groups (i)        2,4-bis(4-phenoxyphenyl)-1,3,2,4-dithiadiphosphetane        2,4-disulfide, DME, THF; (ii) isopropanol; (iii) Zn, I₂,        Pd₂(dba)₃,        dicyclohexyl(2′,6′-dimethoxy-[1,1′-biphenyl]-2-yl)phosphine,        DMF; (iv) Deprotection of PG₂, e.g., tert-butyl ester        deprotection: DCM, TFA; (v) If Z═CO then coupling with acd: base        (DIEA, TEA, or NMM), coupling reagents (EDC, HOBt or DCC, HOBt,        or DCC, DMAP or HATU), solvent (DMF or DCM); If Z═SO₂ then        coupling with sulfonyl-Cl: DIEA or TEA, DCM or DMF; (vi)        Deprotection of PG₁, e.g., methyl ester deprotection: NaOH,        MeOH, water.

The other enantiomer can be prepared in a similar manner using Scheme13.

-   -   Reagents: PG₁ and PG₂ are protecting groups: (i) Zn, I₂,        Pd₂(dba)₃,        dicyclohexyl(2′,6′-dimethoxy-[1,1′-biphenyl]-2-yl)phosphine,        DMF; (ii) Deprotection of PG₂, e.g., tert-butyl carbonate        deprotection: DCM, TFA; (iii) If Z═CO then coupling with acd:        base (DIEA, TEA, or NMM), coupling reagents (EDC, HOBt or DCC,        HOBt, or DCC, DMAP or HATU), solvent (DMF or DCM); If Z═SO₂ then        coupling with sulfonyl-Cl: DIEA or TEA, DCM or DMF; (iv)        Deprotection of PG₁, e.g., tert-butyl ester deprotection: DCM,        TFA.

The other enantiomer can be prepared in a similar manner using Scheme14.

-   -   Reagents: PG₁ and PG₂ are a protecting group (i)        1,1,3,3-tetramethylguanidine, THF; (ii) H₂, Dioxane; (iii)        Deprotection of PG₁ e.g., boc-amine deprotection: DCM, TFA; (iv)        If Z═CO then coupling with acd: base (DIEA, TEA, or NMM),        coupling reagents (EDC, HOBt or DCC, HOBt, or DCC, DMAP or        HATU), solvent (DMF or DCM); If Z═SO₂ then coupling with        sulfonyl-Cl: DIEA or TEA, DCM or DMF; (v) Deprotection of PG₂,        e.g., tert-butyl ester deprotection: DCM, TFA.

-   -   Reagents: PG₁ and PG₂ are protecting groups (i)        1,1,3,3-tetramethylguanidine, THF; (ii) H₂, Dioxane; (iii)        Deprotection of PG₁ e.g., boc amine deprotection: DCM, TFA; (iv)        If Z═CO then coupling with acid: base (DIEA, TEA, or NMM),        coupling reagents (EDC, HOBt or DCC, HOBt, or DCC, DMAP or        HATU), solvent (DMF or DCM); If Z═SO₂ then coupling with        sulfonyl-Cl: DIEA or TEA, DCM or DMF; (v) Deprotection of PG₂,        e.g., tert-butyl ester deprotection: DCM, TFA.

-   -   Reagents: PG is a protecting group (i)        3-bromo-5-chloro-1,2,4-thiadiazole, NaHCO₃, Pd(dppf)Cl₂, water        and THF, ACN or dioxane; (ii) NaHCO₃, Pd(dppf)Cl₂, water and        THF, ACN or dioxane; (iii) Deprotection of PG, e.g., tert-butyl        ester deprotection: DCM, TFA.

The other enantiomer can be prepared in a similar manner using Scheme17.

-   -   Reagents: PG is a protecting group (i) NaO^(t)Bu or Cs₂CO₃,        Pd(dppf)Cl₂ or Pd₂(dba)₃,        2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl, water        and THF, ACN or dioxane; (ii) Deprotection of PG, e.g.,        tert-butyl ester deprotection: DCM, TFA.

The other enantiomer can be prepared in a similar manner using Scheme18.

-   -   Reagents: PG is a protecting group (i) NaO^(t)Bu or Cs₂CO₃,        Pd₂(dppf)Cl₂ or Pd₂(dba)₃,        2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl, water        and THF, ACN or dioxane; (ii) Deprotection of PG, e.g.,        tert-butyl ester deprotection: DCM, TFA.

The other enantiomer can be prepared in a similar manner using Scheme19.

-   -   Reagents: PG is a protecting group (i) NaO^(t)Bu or Cs₂CO₃,        Pd(dppf)Cl₂ or Pd₂(dba)₃,        2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl, water        and THF, ACN or dioxane; (ii) Deprotection of PG, e.g.,        tert-butyl ester deprotection: DCM, TFA.

The other enantiomer can be prepared in a similar manner using Scheme20.

-   -   Reagents: PG is a protecting group (i) (a) where R₂ is        NH—(CR_(a)R_(b))_(m)—COOH: NH₂—(CR_(a)R_(b))_(m)—COOPG, HATU,        DMF then deprotection e.g., tert-butyl ester deprotection: DCM,        TFA; (b) where R₂ is NH—SO₂—R₈: R₈SO₂NH₂, DCC, DMAP, DCM (c)        where R₂ is NR₄₁R₄₂: HNR₄₁R₄₂, HATU, DMF then deprotection e.g.,        tert-butyl ester deprotection: DCM, TFA: (d) where R₂ is        N(R₁)—(CR_(a)R_(b))_(m)—CO—N(R₁)-heterocyclyl:        HN(R₁)—(CR_(a)R_(b))_(m)—CO—N(R₁)-heterocyclyl, HATU, DMF then        deprotection e.g., tert-butyl ester deprotection: DCM, TFA; (e)        where R₂ is —N(R₁)—(CR_(a)R_(b))_(m)—CO—N(R₁)(R₇):        NH₂—(CR_(a)R_(b))_(m)—COOPG, HATU, DMF then deprotection e.g.,        tert-butyl ester deprotection: DCM, TFA then HN(R₁)(R₇), HATU,        DMAP, DCM (f) where R₂ is N(R₁)-heterocyclyl:        HN(R₁)-heterocyclyl, HATU, DMF then deprotection e.g.,        tert-butyl ester deprotection: DCM, TFA.

The other enantiomer and diasteroisomer can be prepared in a similarmanner using Scheme 21.

-   -   Reagents: PG₁ and PG₂ are protecting groups (i) DIEA,        1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide,        DCM; (ii) KOAc, bis-pinacolatoborane, PdCl₂(dppf); (iii)        Pd(dppf)Cl₂, Na₂CO₃, THF, MeCN, water; (iv) Pd(dppf)Cl₂, Na₂CO₃,        THF, MeCN, water; (v) Deprotection of PG₂, eg CBZ: Pd/C, H₂,        EA; (vi) If Z═CO then Amide coupling with acid-Cl: DIEA, DCM or        amide coupling with acid: EDC, HOBt, DMF or HATU, DMF; If Z═SO₂,        then coupling with sulfonyl chloride: DIEA or NEt₃, DCM or        DMF; (vii) Deprotection of PG₁, e.g., tert-butyl ester        deprotection: DCM, TFA.

The other enantiomer can be prepared in a similar manner using Scheme22.

-   -   Reagents: PG is a protecting group (i) Pd(dppf)Cl₂, Na₂CO₃, THF,        MeCN, water; (ii) Deprotection of PG, e.g., tert-butyl ester        deprotection: DCM, TFA.

The other enantiomer can be prepared in a similar manner using Scheme23.

-   -   Reagents: PG is a protecting group (i) Zn(CN)₂, Pd(Ph₃)₄,        NMP; (ii) hydroxylamine, NEt₃, EtOH; (iii) EDC, HOBt, DMF then        heat; (iv) Deprotection of PG, e.g., tert-butyl ester        deprotection: DCM, TFA.

The other enantiomer can be prepared in a similar manner using Scheme24.

-   -   Reagents: PG is a protecting group (i) NH₄Cl, NaN₃, DMF; (ii)        CsCO₃, or K₂CO₃, DMF, acetone or acetonitrile; (iii)        Deprotection of PG, e.g., tert-butyl ester deprotection: DCM,        TFA.

The other enantiomer can be prepared in a similar manner using Scheme25.

-   -   Reagents: PG is a protecting group (i) sodium tert-butoxide,        Pd₂(dba)₃, dioxane; (ii) Deprotection of PG, e.g., tert-butyl        ester deprotection: DCM, TFA.

The other enantiomer can be prepared in a similar manner using Scheme26.

-   -   Reagents: PG is a protecting group (i) NaO^(t)Bu or Cs₂CO₃,        Pd₂(dppf)Cl₂ or Pd₂(dba)₃,        2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl, water        and THF, ACN or dioxane; (ii) Pd/C, H₂, EtOH, (iii) Deprotection        of PG, e.g., tert-butyl ester deprotection: DCM, TFA.

The other enantiomer can be prepared in a similar manner using Scheme27.

EXAMPLES

The invention is further illustrated by the following examples. Theexamples below are non-limiting are merely representative of variousaspects of the invention.

General Methods NMR Spectra

¹H NMR (400 MHz) and ¹³C NMR (100 MHz) were obtained in solution ofdeuteriochloroform (CDCl₃) or dimethyl sulfoxide (d₆-DMSO). NMR spectrawere processed using MestReNova 6.0.3-5604.

LCMS Data

Mass spectra (LCMS) were obtained using one of 5 systems. System 1:Agilent 1100/6110 HPLC system equipped with a Thompson ODS-A, 100 A, 5μ(50×4.6 mm) column using water with 0.1% formic acid as the mobile phaseA, and acetonitrile with 0.1% formic acid as the mobile phase B. Method1: 20-100% mobile phase B over 2.5 min then held at 100% for 2.5 minwith a flow rate of 1 mL/min. Method 2: 5% mobile phase B for 1 min,5-95% over 9 min, then held at 95% for 10 min, with a flow rate of 1mL/min. Method 3: 20-100% mobile phase B over 2.5 min then held at 100%for 4.5 min with a flow rate of 1 mL/min. System 2: Agilent 1200 LCMSequipped with an Agilent Zorbax Extend RRHT 1.8 μm (4.6×30 mm) columnusing water with 0.1% formic acid as mobile phase A and acetonitrilewith 0.1% formic acid as mobile phase B. Method 4: 5-95% mobile phase Bover 3.0 min with a flow rate of 2.5 mL/min, then held at 95% for 0.5min with a flow rate of 4.5 mL/min. Method 5: 5-95% mobile phase B over14 min with a flow rate of 2.5 mL/min, then held at 95% for 0.5 min withan flow rate of 4.5 mL/min. System 3: Waters Fractionlynx LCMS systemequipped with an Agilent Zorbax Extend RRHT 1.8 μm, (4.6×30 mm) columnusing water with 0.1% formic acid as mobile phase A and acetonitrilewith 0.1% formic acid as mobile phase B. Method 6: 5-95% mobile phase Bover 3.0 min with a flow rate of 2.5 mL/min, then held at 95% for 0.5min with a flow rate of 4.5 mL/min. Method 7: 5-95% mobile phase B over14 min with a flow rate of 2.5 mL/min, then held at 95% for 0.5 min withan flow rate of 4.5 mL/min. System 4: Agilent 1260 LCMS equipped with anAgilent Zorbax Extend RRHT 1.8 μm (4.6×30 mm) column using water with0.1% formic acid as mobile phase A and acetonitrile with 0.1% formicacid as mobile phase B. Method 8: 5-95% mobile phase B over 3.0 min witha flow rate of 2.5 mL/min, then held at 95% for 0.5 min with a flow rateof 4.5 mL/min. Method 9: 5-95% mobile phase B over 14 min with a flowrate of 2.5 mL/min, then held at 95% for 0.5 min with an flow rate of4.5 mL/min. System 5: Agilent 1260 LCMS equipped with a Waters XselectCSH C18 3.5 μm (4.6×50 mm) column using water with 0.1% formic acid asmobile phase A and acetonitrile with 0.1% formic acid as mobile phase B.Method 10: The gradient was 5-95% mobile phase B over 13.0 min with aflow rate of 2.5 mL/min, then held at 95% for 1.0 min with an flow rateof 4.5 mL/min. Method 11: The gradient was 5-95% mobile phase B over 3.0min with a flow rate of 2.5 mL/min, then held at 95% for 0.6 min with anflow rate of 4.5 mL/min.

Reaction Conditions and Abbreviations

Pyridine, dichloromethane (DCM), tetrahydrofuran (THF), and toluene usedin the procedures were from Aldrich Sure-Seal bottles or Acros AcroSealdry solvent and kept under nitrogen (N₂). All reactions were stirredmagnetically and temperatures are external reaction temperatures.Compounds with salt-able centers were presumed to be the trifluoroaceticacid (TFA) salt. The following abbreviations are used: ethyl acetate(EA), 1-methyl-2-pyrrolidinone (NMP), triethylamine (TEA),N-hydroxybenzotriazole (HOBt), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC), N,N-dimethylformamide (DMF), dimethylacetamide (DMA), Di-tert-butyl dicarbonate (Boc₂O),N,N-Diisopropylethylamine (DIEA), acetic acid (AcOH), hydrochloric acid(HCl), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU), 4-dimethylaminopyridine (DMAP), tert-butanol(t-BuOH), sodium hydride (NaH), sodium triacetoxyborohydride(Na(OAc)₃BH), ethanol (EtOH), methanol (MeOH), acetonitrile (ACN).

Purifications

Chromatographies were carried out using either a Combiflash Rf flashpurification system (Teledyne Isco) equipped with Redisep (TeledyneIsco), Telos (Kinesis) or GraceResolv (Grace Davison Discovery Sciences)silica gel (SiO₂) columns. Preparative HPLC purifications were performedusing one of two systems. System 1: Varian ProStar/PrepStar systemequipped with a Waters SunFire Prep C18 OBD, 5 μm (19×150 mm) columnusing water containing 0.05% trifluoroacetic acid as mobile phase A, andacetonitrile with 0.05% trifluoroacetic acid as mobile phase B. Thegradient was 40-95% mobile phase B over 10 min, held at 95% for 5-10min, and then return to 40% over 2 min with flow rate of 18 mL/min.Fractions were collected using a Varian Prostar fraction collector by UVdetection at 254 nm and were evaporated using a Savant SpeedVac Plusvacuum pump or a Genevac EZ-2. System 2: Waters Fractionlynx systemequipped with an Agilent Prep-C 18, 5 μm (21.2×50 mm) column using watercontaining 0.1% formic acid as mobile phase A, and acetonitrile with0.1% formic acid as mobile phase B. The gradient was 45-95% mobile phaseB over 7.5 min, held at 95% for 1 min, and then returned to 45% over 1.5min with a flow rate of 28 mL/min. Fractions were collected by UVdetection at 254 nm or by mass and evaporated using a Genevac EZ-2.

Chiral Methods

Enantiomeric excess was determined by integration of peaks that wereseparated on a Diacel Chiralpak IA, 4.6×250 mm column, 5 μm particlesize. The solvents used were “Solvent A”: 4:1 (hexanes with 0.2% TFA):DCM, and “Solvent B”: EtOH. The flow rate was held at 1.0 mL/min withthe following gradient: Increase Solvent B from 2-10% over 30 min, holdSolvent B at 10% for 15 min.

Experimental Procedures General Procedures General Procedure 1:Preparation of Nitriles.

A stirred a solution of bromide or triflate (1 eq), zinc cyanide (2 eq)and tetrakis (triphenylphosphine) palladium (1-5 mol %) in dry NMP(0.5-1 M) was degassed with N₂. The reaction was heated to 100° C. for18 h while stirring under N₂. The reaction mixture was cooled and pouredinto water and DCM. The solid material was removed by filtration and thefiltrate was extracted with water. The organic layer was dried overMgSO₄ and concentrated. The crude product was purified bychromatography.

General Procedure 2: Preparation of Amidoximes.

To a stirring solution of nitrile (1 eq) in EtOH was added hydroxylamine(50% solution in H₂O, 5 eq) and TEA (1.1 eq). The mixture was heated for2-12 h at 80-85° C. then concentrated. The resulting solid was dissolvedin EA, washed with water, then dried with Na₂SO₄, concentrated and usedwithout further purification. Alternatively, to a stirring solution ofnitrile (1 eq) and TEA (2-3 eq) in DMF or EtOH was added hydroxylaminehydrochloride (2-3 eq). The mixture was stirred at RT up to 80° C. forup to 24 h then concentrated. The resulting solid was dissolved in EA orDCM, washed with water or brine, then dried with Na₂SO₄, concentrated,and used without further purification.

General Procedure 3: Preparation of Amides Via Acid Chlorides.

To a solution of amine (1 eq) and base (either DIEA or TEA) (2-3 eq) inDCM (0.06-0.30 M) was treated with the appropriate acid chloride(1.0-1.5 eq). The reaction mixture was stirred until the reaction wascomplete. The reaction was diluted with DCM and washed with saturatedaqueous NaHCO₃. The organic layer was dried over MgSO₄ and concentrated.The product was purified by chromatography. Alternatively, the crudereaction mixture can be carried on to the next step without furtherpurification.

General Procedure 4: Hydrolysis of Esters to Acids.

To a stirring solution of ester (1 eq) in THF or dioxane and water, wasadded NaOH or LiOH (1-3 eq). The reaction mixture was stirred at up to60° C. for up to 18 h. The reaction mixture was neutralized with AcOH orHCl and either diluted with water or concentrated. If the reactionmixture was diluted with water, then HCl was added to acidify thereaction mixture to a pH of approximately 2. The resulting precipitatewas isolated by filtration to yield product which can be purified bychromatography, preparative HPLC, or used without purification. If thereaction mixture was concentrated, the crude material was diluted withDCM or EA and washed with brine. The organic layer was concentrated andpurified by chromatography or preparative HPLC to give final product.Alternatively, the crude material can be carried forward withoutpurification.

General Procedure 5: Preparation of Oxadiazoles via Acids or AcidChlorides. Oxadiazoles Via Acids:

To a solution of acid (1 eq) in DMF was added HOBt (2 eq) and EDC (2eq). After stirring for 2 h, amidoxime (2 eq) was added and the mixturewas stirred at RT for up to 12 h. The reaction mixture was then heatedto 100° C. for up to 12 h. Alternatively, after stirring at RT, thereaction mixture was diluted with DCM, washed with NaHCO₃, then driedwith Na₂SO₄ and concentrated. The resulting residue was dissolved inEtOH and heated in a microwave for 35 min at 110° C. The solvent wasremoved and the final product was purified by preparative HPLC.

Oxadiazoles Via Acid Chlorides:

To synthesize oxadiazoles via acid chlorides, dioxanes and DIEA (1.5 eq)were added to a stirred solution of amidoxime (1 eq) followed by an acidchloride (1.1 eq). The reaction mixture was stirred at RT for 30 minthen at 120° C. for up to 6 h. The reaction mixture was allowed to coolto RT, diluted with EA and washed with brine. The organics wereconcentrated and the residue purified by chromatography.

General Procedure 6: Removal of tert-Butyl Carbamate.

A solution of the tert-butyl carbamate (1 eq) in DCM (0.06 M) wastreated with TFA (0.16-0.33 M). The reaction mixture was stirred ateither RT or 30° C. until complete. The solvent was removed and theproduct was purified by chromatography or preparative HPLC.

General Procedure 7: Preparation of Amides Via Peptide Coupling.

A solution of amine (1.0 eq) and base (DIEA, TEA or NMM) (0-3.0 eq) inDCM or DMF (0.08-0.10 M) was treated with the appropriate carboxylicacid (1.0-1.5 eq). To this mixture was added the coupling reagent. Thecoupling reagent could be HATU (1.05-2.5 eq), EDC (1.5 eq) with HOBt(1.5 eq), DCC (1.1 eq) with HOBt (1.1 eq) or DCC (1.5 eq) with DMAP (2.0eq). The reaction mixture was stirred until the reaction was complete.The reaction was diluted with EA and washed with saturated aqueousNaHCO₃. The organic layer was dried over MgSO₄ and concentrated. Theproduct was purified by chromatography or alternatively can be carriedon to the next step without further purification.

General Procedure 8: Deprotection of t-Butyl Esters to Acids orDeprotection of Boc-Amines

A solution of the tert-butyl ester or Boc-amine (1.00 eq) in DCM (0.06M) was treated with TFA (0.16-0.33 M). The reaction mixture was stirredat either RT or 30° C. until complete. The solvent was removed and theproduct was purified by chromatography or preparative HPLC.

General Procedure 9: Formation of Triflate.

A solution of the phenol (1.0 eq) in DCM (0.25 M) was treated with1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide(1.1 eq). The reaction mixture was stirred at RT until complete. Thereaction was stirred with water and saturated aqueous NaHCO₃. Theorganic layers was dried and concentrated. The material was purified bychromatography or alternatively used without purification.

Procedure 10: Palladium-Catalyzed Coupling Reactions.

A solution of boronic acid or boronate ester (1.0-1.3 eq), halide(1.0-1.3 eq), sodium bicarbonate or sodium carbonate decahydrate(2.0-2.5 eq), and Pd(dppf)Cl₂ were combined in THF, acetonitrile, ordioxane (0.1-0.2 M) and water (0.25-0.50 M). The reaction was heated at80 to 100° C. until complete. The reaction was diluted with EA andwashed with saturated aqueous NaHCO₃. The organic layer was dried overMgSO₄ and concentrated. The product can be purified by chromatography,preparative HPLC, or carried on to the next step without furtherpurification.

General Procedure 11: Palladium-Catalyzed Aryl Amidation.

A solution of aryl bromide or triflate (1.00 eq), sodium tert-butoxideor cesium carbonate (1-2 eq) and amine (1.0-1.5 eq) in dioxane or THF(0.05M) was degassed using N₂ bubbling for 10 min. Pd₂(dba)₃ (0.10 eq)and 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (0.15 eq) areadded and the reaction mixture was heated for 45-60 min at 100-120° C.in a microwave reactor or up to 80° C. with conventional heating for upto 18 h. The reaction was diluted with EA and washed with saturatedaqueous NaHCO₃. The organic layer was dried over Na₂SO₄ andconcentrated. The product can be purified by chromatography, preparativeHPLC, or carried on to the next step without further purification.

General Procedure 12: Alkylation of Phenols, Imidazoles, and Lactams.

To a solution of a phenolic intermediate in DMF, acetone or ACN (0.1 M)were added the appropriate bromoalkane (1.5 eq) and either CsCO₃(1.5-2.0 eq) or K₂CO₃ (1.5-2.0 eq). The reaction mixture was heated at40-70° C. for 18 h, then diluted with DCM and washed with H₂O. Theorganic layer was dried over Na₂SO₄ and concentrated. The product can bepurified by chromatography, preparative HPLC, or carried on to the nextstep without further purification.

General Procedure 13: Sulfonate or Sulfonamide Formation.

To a solution of alcohol or amine in DCM (0.02 M) was added the sulfonylchloride (2 eq) and triethylamine (3 eq). The reaction was stirred at RTuntil complete. The reaction was diluted with DCM and washed withsaturated aqueous NaHCO₃. The organic layer was dried over MgSO₄ andconcentrated. The product can be purified by chromatography, preparativeHPLC, or carried on to the next step without further purification.

General Procedure 14: Reduction of Aryl Nitro to an Aryl Amine.

To a stirring solution of aryl nitro (1 eq) in THF purged with N₂ wasadded palladium on carbon. The reaction mixture was subjected to an H₂atmosphere for up to 4 h. The reaction mixture can be filtered over apad of celite and solvent concentrated. The crude material was carriedforward without further purification.

General Procedure 15: Preparation of a Secondary or Tertiary Amine ViaReductive Amination.

To a stirring solution of aldehyde or ketone (0.9-1.0 eq) in DCM or1,2-dichloroethane or THF was added an amine (0.9-1.1 eq). Afterstirring at RT for up to 2 h, one drop of acetic acid (optional) wasadded followed by sodium triacetoxyborohydride (1.5-2.0 eq) and thereaction mixture was stirred overnight. In some cases it is necessary tofilter the reaction mixture, redissolve and add additional reducingagent to drive the reaction to completion. The crude reaction mixturewas quenched with NaHCO₃ and stirred for 5 min. The aqueous layer wasextracted with DCM and the organic layer was dried over MgSO₄ andconcentrated. The final product was isolated by chromatography.

General Procedure 16: Preparation of 2-Iodopyrimidines

To a stirred solution of a 2-chloro pyrimidine (1 eq) in 57% aqueoushydrogen iodide (1 mL) was added sodium iodide (2 eq). The reactionmixture was stirred at ambient temperature until the starting materialwas consumed. The reaction mixture was quenched with NaHCO₃ (5 mL) thenextracted with EA (3×5 mL). The combined organic layer was washed withbrine (10 mL), dried over MgSO₄ and concentrated. The crude product wasused in the subsequent step without purification.

General Procedure 17. Preparation of 2-Iodopyridines

To a stirred solution of a 2-chloropyridine (1 eq) in acetonitrile (2mL) was added sodium iodide (6 eq). The reaction mixture was heated to40° C. and acetyl chloride (0.6 eq) was added. The reaction mixture wasstirred until the staring material was consumed. The reaction wasquenched with NaHCO₃ (5 mL) and extracted with EA (3×5 mL). The combinedorganic layer was washed with brine (10 mL), dried over MgSO₄ andconcentrated. The crude product was used in the subsequent step withoutpurification.

Synthesis of Representative Compounds 4-(heptyloxy)benzonitrile

Prepared using General Procedure 1: A stirred a solution of1-bromo-4-(heptyloxy)benzene (2.0 g, 7.37 mmol), zinc cyanide (1.73 g,14.74 mmol) and tetrakis (triphenylphosphine) palladium (76.12 mg, 0.07mol) in dry NMP (20 mL) was degassed with N₂. The reaction was heated to100° C. for 18 h while stirring under nitrogen. The reaction mixture wascooled and poured into water (100 mL) and DCM (20 mL). The solidmaterial was removed by filtration and the filtrate was extracted withwater (3×20 mL). The organic layer was dried over MgSO₄ andconcentrated. The crude product was purified by chromatography(EA/hexanes) to afford 1.15 g (73%) of 4-(heptyloxy)benzonitrile as alight yellow solid. LCMS-ESI (m/z) calculated for C₁₄H₁₉NO: 217.1; found218.1 [M+H]⁺, t_(R)=11.14 min (Method 2). ¹H NMR (400 MHz, CDCl₃) δ7.64-7.50 (m, 2H), 7.05-6.83 (m, 2H), 3.99 (t, J=6.5 Hz, 2H), 1.89-1.69(m, 2H), 1.58-1.12 (m, 8H), 0.90 (dd, J=9.1, 4.5 Hz, 3H). ¹³C NMR (101MHz CDCl₃) δ 162.47, 133.91, 132.78, 132.12, 129.13, 119.31, 115.18,103.58, 68.41, 31.73, 28.98, 25.89, 22.58, 14.07.

(Z)-4-(heptyloxy)-N′-hydroxybenzimidamide

Prepared using General Procedure 2: To a stirring solution of4-(heptyloxy)benzonitrile (1.0 g, 4.6 mmol) in EtOH (15 mL) were addedhydroxylamine hydrochloride (0.96 g, 13.8 mmol) and TEA (2.22 g, 23.0mmol). The reaction was heated to 85° C. for 2 h. The solvent wasremoved under reduced pressure and the residue was diluted with water(20 mL) and extracted with DCM (3×10 mL). The combined organic layerswere concentrated under reduced pressure. The crude material wascrystallized from isopropanol (20 mL) to afford 1.05 g (91%) of(Z)-4-(heptyloxy)-N-hydroxybenzimidamide as a white solid. LCMS-ESI(m/z) calculated for C₁₄H₂₂N₂O₂: 250.2; found 251.3 [M+H]⁺, t_(R)=1.70min (Method 1). ¹H NMR (400 MHz, CDCl₃) δ 9.45 (s, 1H), 7.59 (d, J=8.6Hz, 2H), 6.93 (t, J=14.7 Hz, 2H), 5.82-5.48 (m, 2H), 3.97 (t, J=6.5 Hz,2H), 1.83-1.55 (m, 2H), 1.56-1.05 (m, 8H), 0.87 (t, J=6.7 Hz, 3H). ¹³CNMR (101 MHz CDCl₃) δ 159.19, 150.53, 126.64, 125.55, 113.87, 67.40,31.21, 28.62, 28.40, 25.44, 22.02, 13.92.

(S)-methyl 4-(2-amino-3-methoxy-3-oxopropyl)benzoate

To a solution of (S)-2-amino-3-(4-(tert-butoxycarbonyl)phenyl)propanoicacid (500.0 mg, 1.88 mmol) in MeOH (20 mL) at 0° C. was slowly addedthionyl chloride (447.64 mg, 3.77 mmol). The reaction was stirred for 1h at 0° C. then warmed to RT and stirred for 1 h. The solvent wasremoved under reduced pressure. The reaction mixture was washed withsaturated aqueous NaHCO₃ (20 ml) and extracted with DCM (3×10 ml). Theorganic layer was dried over MgSO₄ and concentrated. The crude productwas purified by chromatography (EA/hexanes) to afford 425 mg (95%) of(S)-methyl 4-(2-amino-3-methoxy-3-oxopropyl)benzoate as the HCl salt.LCMS-ESI (m/z) calculated for C₁₂H₁₅NO₄: 237.1; found 238.0 [M+H]⁺,t_(R)=1.01 min (Method 1). ¹H NMR (400 MHz, CDCl₃) δ 8.55 (s, 3H), 7.94(d, J=8.3 Hz, 2H), 7.41 (d, J=8.3 Hz, 2H), 4.37 (t, J=6.8 Hz, 1H), 3.86(s, 3H), 3.68 (s, 3H), 3.20 (dd, J=11.8, 6.8 Hz, 2H).

(S)-methyl 4-(2-(4-(tert-butyl)benzamido)-3-methoxy-3-oxopropyl)benzoate

Prepared using General Procedure 3: To the solution of (S)-methyl4-(2-amino-3-methoxy-3-oxopropyl)benzoate (425.0 mg, 1.79 mmol) in DCM(10 mL) and DIEA (463.0 mg, 3.58 mmol) was added 4-(tert-butyl)benzoylchloride (556.6 mg, 2.83 mmol) at RT. The reaction was stirred for 2 hand the reaction was partitioned between DCM and saturated aqueousNaHCO₃. The organic layer was dried over MgSO₄ and concentrated. Thecrude product was purified by chromatography (EA/hexanes) to afford 317mg (45%) of (S)-methyl4-(2-(4-(tert-butyl)benzamido)-3-methoxy-3-oxopropyl)benzoate. LCMS-ESI(m/z) calculated for C₂₃H₂₇NO₅: 397.2; found 398.1 [M+H]⁺, t_(R)=2.31min (Method 1). ¹H NMR (400 MHz, CDCl₃) δ 7.97-7.75 (m, 2H), 7.67-7.51(m, 2H), 7.46-7.26 (m, 2H), 7.14 (d, J=8.3 Hz, 2H), 6.60 (d, J=7.4 Hz,1H), 5.03 (dt, J=7.4, 5.7 Hz, 1H), 3.82 (s, 3H), 3.68 (s, 3H), 3.28 (dd,J=13.7, 5.8 Hz, 1H), 3.18 (dd, J=13.7, 5.5 Hz, 1H), 1.24 (s, 9H).

(S)-4-(2-(4-(tert-butyl)benzamido)-3-methoxy-3-oxopropyl)benzoic acid(INT-1)

Prepared using General Procedure 4: To a stirred solution of (S)-methyl4-(2-(4-(tert-butyl)benzamido)-3-methoxy-3-oxopropyl)benzoate (316.6 mg,0.79 mmol) in dioxane (15 mL) and water (1 mL) at 0° C. was addedlithium hydroxide monohydrate (93.52 mg, 2.23 mmol). After 2 h, thesolution was neutralized with 1 M HCl to pH 7.0. The mixture waspartitioned between DCM (15 mL) and saturated aqueous NaHCO₃ (10 mL).The organic layer was washed with saturated aqueous NaHCO₃ (3×10 mL) andbrine (10 mL). The organic layer was dried over MgSO₄ and concentratedto afford 208 mg (69%) of(S)-4-(2-(4-(tert-butyl)benzamido)-3-methoxy-3-oxopropyl)benzoic acidINT-1. LCMS-ESI (m/z) calculated for C₂₂H₂₅NO₅: 383.2; found 384.1[M+H]⁺, t_(R)=2.13 min. (Method 1). ¹H NMR (400 MHz, DMSO) δ 12.86 (s,1H), 8.80 (d, J=8.0 Hz, 1H), 7.87-7.78 (m, 2H), 7.75-7.65 (m, 2H),7.50-7.35 (m, 4H), 4.72 (ddd, J=10.3, 8.0, 5.1 Hz, 1H), 3.65 (s, 3H),3.28-3.05 (m, 2H), 1.29 (s, 9H). ¹³C NMR (101 MHz, DMSO) δ 173.00,167.21, 166.29, 154.39, 143.10, 130.85, 129.34, 129.27, 129.21, 129.03,127.21, 125.39, 125.10, 53.75, 52.04, 34.64, 30.92, 30.88.

(S)-methyl2-(4-(tert-butyl)benzamido)-3-(4-(3-(4-(heptyloxy)phenyl)-1,2,4-oxadiazol-5-yl)phenyl)propanoate

Prepared using General Procedure 5: To a solution of(S)-4-(2-(4-(tert-butyl)benzamido)-3-methoxy-3-oxopropyl)benzoic acid,INT-1 (10.0 mg, 0.026 mmol) in anhydrous DMF (1 mL) was added HOBt (5.27mg, 0.39 mmol) and EDC (7.48 mg, 0.39 mmol). After stirring for 2 h,(Z)-4-(heptyloxy)-N′-hydroxybenzimidamide (9.76 mg, 0.39 mmol) wasadded. The reaction mixture was stirred at RT for 2 h, partitionedbetween saturated aqueous NaHCO₃ (5 ml) and EA (5 mL), and concentratedunder reduced pressure to afford the intermediate (S)-methyl2-(4-(tert-butyl)benzamido)-3-(4-(((4-(heptyloxy)benzimidamido)oxy)carbonyl)phenyl) propanoate. The intermediate was dissolved in DMF (1 mL) andheated to 100° C. for 18 h. The reaction mixture was cooled to RT andpartitioned between EA (5 mL) and saturated aqueous NaHCO₃ (5 mL). Theorganic layer was extracted with water (2×5 mL) and brine (5 mL). Theorganic layer was dried over MgSO₄ and concentrated. The brown oil waspurified by preparative HPLC to afford 4.5 mg (29%) of (S)-methyl2-(4-(tert-butyl)benzamido)-3-(4-(3-(4-(heptyloxy)phenyl)-1,2,4-oxadiazol-5-yl)phenyl) propanoate. LCMS-ESI (m/z) calculated for C₃₆H₄₃N₃O₅: 597.3; nom/z observed, t_(R)=12.75 min (Method 2). ¹H NMR (400 MHz, DMSO) δ 8.85(d, J=8.0 Hz, 1H), 8.09 (d, J=8.3 Hz, 2H), 8.00 (d, J=8.9 Hz, 2H), 7.74(d, J=8.5 Hz, 2H), 7.59 (d, J=8.4 Hz, 2H), 7.48 (d, J=8.6 Hz, 2H), 7.12(d, J=8.9 Hz, 2H), 4.87-4.56 (m, 1H), 4.06 (t, J=6.5 Hz, 2H), 3.67 (s,3H), 3.32-3.13 (m, 4H), 1.74 (dd, J=14.2, 6.5 Hz, 2H), 1.51-1.37 (m,2H), 1.33 (s, 4H), 1.26 (d, J=20.2 Hz, 9H), 0.88 (t, J=6.9 Hz, 3H). ¹³CNMR (101 MHz, DMSO) δ 175.00, 171.91, 167.89, 166.27, 161.21, 154.37,143.68, 130.78, 130.30, 128.76, 127.80, 127.18, 125.07, 121.69, 118.21,115.07, 67.72, 53.61, 52.05, 36.15, 34.60, 31.20, 30.87, 28.54, 28.39,25.40, 22.02, 13.93.

(S)-2-(4-(tert-butyl)benzamido)-3-(4-(3-(4-(heptyloxy)phenyl)-1,2,4-oxadiazol-5-yl)phenyl)propanoicacid (Compound 1)

Prepared using General Procedure 4: To a solution of (S)-methyl2-(4-(tert-butyl)benzamido)-3-(4-(3-(4-(heptyloxy)phenyl)-1,2,4-oxadiazol-5-yl)phenyl)propanoate (4.52 mg, 0.008 mmol) in MeOH (2 mL) was added of 1 N NaOH (1mL). The reaction mixture was stirred at 50° C. for 3 h. The resultingmixture was purified by preparative HPLC to afford 0.36 mg (8%) of(S)-2-(4-(tert-butyl)benzamido)-3-(4-(3-(4-(heptyloxy)phenyl)-1,2,4-oxadiazol-5-yl)phenyl)propanoic acid. LCMS-ESI (m/z) calculated for C₃₅H₄₁N₃O₅: 583.7; no m/zobserved, t_(R)=12.59 min (Method 2).

(S)-methyl 2-amino-3-(4-cyanophenyl)propanoate

To a solution of(S)-2-((tert-butoxycarbonyl)amino)-3-(4-cyanophenyl)propanoic acid (1.0g, 3.44 mmol) in MeOH (20 mL) at 0° C. was slowly added thionyl chloride(818.1 mg, 6.89 mmol) over 1 h. The reaction was warmed to RT andstirred for 1 h. The solvent was removed under reduced pressure. Thereaction mixture was washed with saturated aqueous NaHCO₃ (20 ml) andextracted with DCM (3×10 ml). The organic layer was dried over MgSO₄ andconcentrated. The crude product was purified by chromatography(EA/hexanes) to afford 789 mg (97%) of (S)-methyl2-amino-3-(4-cyanophenyl)propanoate as the HCl salt. LCMS-ESI (m/z)calculated for C₁₁H₁₂N₂O₂: 204.1; found 205.0 [M+H]⁺, t_(R)=3.25 min(Method 1). ¹H NMR (400 MHz, CDCl₃) δ 8.69 (s, 3H), 7.83 (d, J=8.3 Hz,2H), 7.51 (t, J=8.8 Hz, 2H), 4.37 (t, J=6.7 Hz, 1H), 3.68 (s, 3H), 3.23(qd, J=14.4, 7.7 Hz, 2H).

(S)-methyl 2-(4-(tert-butyl)benzamido)-3-(4-cyanophenyl)propanoate

Prepared using General Procedure 3: To the solution of (S)-methyl2-amino-3-(4-cyanophenyl)propanoate (789.2 mg, 3.32 mmol) in DCM (15 mL)and DIEA (1.29 g, 9.96 mmol) was added 4-(tert-butyl)benzoyl chloride(981.3 mg, 4.99 mmol) at RT. The reaction was stirred for 2 h and thereaction was partitioned between DCM and saturated aqueous NaHCO₃. Theorganic layer was dried over MgSO₄ and concentrated. The crude productwas purified by chromatography (EA/hexanes) to afford 1.06 g (88%) of(S)-methyl 2-(4-(tert-butyl)benzamido)-3-(4-cyanophenyl)propanoate.LCMS-ESI (m/z) calculated for C₂₂H₂₄N₂O₃: 364.2; found 365.3 [M+H]⁺,t_(R)=3.55 min (Method 1). ¹H NMR (400 MHz, CDCl₃) δ 8.81 (d, J=8.0 Hz,1H), 7.85-7.60 (m, 4H), 7.49 (dd, J=15.1, 8.4 Hz, 4H), 4.85-4.60 (m,1H), 3.65 (s, 3H), 3.30-3.23 (m, 1H), 3.18 (dd, J=13.7, 10.6 Hz, 1H),1.29 (s, 9H).

(S,Z)-methyl 2-(4-(tert-butyl)benzamido)-3-(4-(N′-hydroxycarbamimidoyl)phenyl) propanoate (INT-2)

Prepared using General Procedure 2: To a stirring solution (S)-methyl2-(4-(tert-butyl)benzamido)-3-(4-cyanophenyl)propanoate (1.0 g, 2.74mmol) in EtOH (15 mL) were added hydroxylamine hydrochloride (572.2 mg,8.22 mmol) and TEA (1.38 g, 13.7 mmol). The reaction was heated to 85°C. for 2 h. The solvent was removed under reduced pressure and theresidue was diluted with water (20 mL) and extracted with DCM (3×10 mL).The combined organic layers were concentrated under reduced pressure.The crude material was crystallized from isopropanol (20 mL) to afford1.04 g (95%) of (S,Z)-methyl2-(4-(tert-butyl)benzamido)-3-(4-(N-hydroxycarbamimidoyl)phenyl)propanoateINT-2 as a white solid. LCMS-ESI (m/z): calcd for: C₂₂H₂₇N₃O₄, 397.2;found 398.1 [M+1]⁺, t_(R)=2.26 min (Method 1). ¹H NMR (400 MHz, DMSO) δ10.19 (s, 1H), 9.57 (s, 1H), 8.78 (d, J=7.9 Hz, 1H), 7.74 (d, J=8.4 Hz,2H), 7.58 (d, J=8.2 Hz, 2H), 7.48 (d, J=8.4 Hz, 2H), 7.30 (d, J=8.3 Hz,2H), 4.79-4.49 (m, 1H), 3.65 (s, 3H), 3.15 (dt, J=13.6, 6.0 Hz, 2H),1.75 (d, J=13.6 Hz, 1H), 1.29 (s, 9H).

(S)-methyl2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoate

Prepared using General Procedure 5: To a solution of4-(heptyloxy)benzoic acid (400.0 mg, 1.54 mmol) in anhydrous DMF (6 mL)were added HOBt (312.3 mg, 2.31 mmol) and EDC (442.75 mg, 2.31 mmol).After stirring for 2 h, (S,Z)-methyl2-(4-(tert-butyl)benzamido)-3-(4-(N-hydroxycarbamimidoyl)phenyl)-propanoate,INT-2 (673.3 mg, 1.69 mmol) was added. The reaction mixture was stirredat RT for 2 h, partitioned between saturated aqueous NaHCO₃ (15 mL) andEA (15 mL), and concentrated under reduced pressure to afford theintermediate (S)-methyl2-(4-(tert-butyl)benzamido)-3-(4-(N-((4-(heptyloxy)benzoyl)oxy)carbamimidoyl)phenyl)propanoate. The intermediate was dissolved in DMF(10 mL) and heated to 100° C. for 18 h. The reaction mixture was cooledto RT and partitioned between EA (10 mL) and saturated aqueous NaHCO₃(50 mL). The organic layer was extracted with water (2×10 mL) and brine(10 mL). The organic layer was dried over MgSO₄ and concentrated. Thebrown oil was purified by chromatography (EA/hexanes) to afford 710 mg(77%) of (S)-methyl2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)-1,2,4-oxadiazol-3-yl)phenyl)-propanoateas a white solid. LCMS-ESI (m/z) calculated for C₃₆H₄₃N₃O₅: 597.3; nom/z observed, t_(R)=12.80 min (Method 2). ¹H NMR (400 MHz, DMSO) δ 8.84(d, J=8.0 Hz, 1H), 8.08 (t, J=17.2 Hz, 2H), 7.97 (dd, J=18.2, 8.5 Hz,2H), 7.74 (d, J=8.5 Hz, 2H), 7.50 (dd, J=18.6, 8.3 Hz, 4H), 7.18 (d,J=8.9 Hz, 2H), 4.85-4.63 (m, 1H), 4.09 (dd, J=13.8, 7.3 Hz, 2H), 3.67(s, 3H), 3.24 (ddd, J=23.8, 15.7, 7.3 Hz, 4H), 2.08 (s, 4H), 1.74 (dd,J=14.1, 6.9 Hz, 2H), 1.42 (dd, J=13.6, 6.3 Hz, 2H), 1.30 (d, J=14.5 Hz,9H), 0.88 (t, J=6.8 Hz, 3H). ¹³C NMR (101 MHz, DMSO) δ 174.05, 170.87,133.81, 165.14, 161.43, 153.21, 140.51, 129.70, 128.85, 128.78, 126.06,125.84, 123.93, 123.39, 114.36, 114.25, 66.86, 52.66, 50.88, 34.32,33.47, 30.06, 29.74, 27.33, 27.24, 24.23, 20.89, 12.80.

(S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoicacid (Compound 2)

Prepared using General Procedure 4: To a solution of (S)-methyl2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoate (710.0 mg, 1.19 mmol) in MeOH (20 mL) was added 1 N NaOH (10mL). The reaction mixture was stirred at 50° C. for 3 h. The resultingmixture was purified by chromatography (DCM/MeOH) to afford 218 mg (31%)of(S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoicacid as a white solid. LCMS-ESI (m/z) calculated for C₃₅H₄₁N₃O₅: 583.3;no m/z observed, t_(R)=12.16 min (Method 2). ¹H NMR (400 MHz, DMSO) δ8.69 (d, J=8.3 Hz, 1H), 8.16-8.02 (m, 2H), 7.98 (d, J=8.3 Hz, 2H), 7.74(d, J=8.5 Hz, 2H), 7.53 (d, J=8.3 Hz, 2H), 7.47 (d, J=8.5 Hz, 2H), 7.18(d, J=9.0 Hz, 2H), 4.70 (ddd, J=10.8, 8.4, 4.5 Hz, 1H), 4.09 (t, J=6.5Hz, 2H), 3.30 (dd, J=13.8, 4.2 Hz, 1H), 3.17 (dd, J=13.8, 10.7 Hz, 1H),1.74 (dd, J=14.5, 6.7 Hz, 2H), 1.42 (dd, J=13.8, 6.1 Hz, 2H), 1.37-1.14(m, 14H), 0.87 (t, J=6.9 Hz, 3H). ¹³C NMR (101 MHz, DMSO) δ 175.16,173.00, 167.96, 166.19, 162.55, 154.18, 142.11, 131.08, 129.95, 129.89,127.14, 126.92, 125.01, 124.39, 115.49, 115.37, 67.98, 53.72, 36.19,34.58, 31.19, 30.89, 28.46, 28.37, 25.36, 22.01, 13.92.

Compounds 3-11 and 13-61 were prepared from (S,Z)-methyl2-(4-(tert-butyl)benzamido)-3-(4-(N-hydroxycarbamimidoyl)phenyl)propanoateINT-2 using General Procedures 5 and 4 sequentially.

Compounds 62-66 were prepared from (S,Z)-methyl2-(4-(tert-butyl)benzamido)-3-(4-(N-hydroxycarbamimidoyl)phenyl)propanoateINT-2 using General Procedures 5, 6, and 4 sequentially.

(S)-2-(2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanamido)aceticacid (Compound 67)

Prepared using General Procedures 7 and 8: To a solution of(S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid, Compound 2 (10.0 mg, 0.017 mmol) in anhydrous DMF (1 mL)was added HOBt (3.52 mg, 0.027 mmol) and EDCI (4.88 mg, 0.027 mmol) atRT. After 2 h, tert-butyl 2-aminoacetate (3.49 mg, 0.027 mmol) was addedand the reaction mixture stirred at RT for 2 h. LCMS analysis showedcomplete conversion to the intermediate. The reaction mixture waspartitioned between NaHCO₃ aqueous (5 ml) and DCM (1 mL), the organiclayer was collected and concentrated by vacuum and then was re-dissolvedin 1 mL of DCM and 0.1 mL of TFA. The mixture was heated to 30° C. for 3h. The final compound was purified by HPLC to afford 9.6 mg (88%) of(S)-2-(2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanamido)aceticacid. LCMS-ESI (m/z) calculated for C₃₇H₄₄N₄O₆: 640.3; no m/z observed,t_(R)=11.51 min (Method 2). ¹H NMR (400 MHz, DMSO) δ: 8.60 (d, J=8.4 Hz,1H), 8.47 (t, J=5.7 Hz, 1H), 8.10 (d, J=8.8 Hz, 2H), 7.96 (d, J=8.2 Hz,2H), 7.75 (d, J=8.4 Hz, 2H), 7.57 (d, J=8.0 Hz, 2H), 7.45 (d, J=8.4 Hz,2H), 7.17 (d, J=8.8 Hz, 2H), 4.83 (d, J=8.1 Hz, 1H), 4.09 (t, J=6.4 Hz,2H), 3.94-3.69 (m, 2H), 3.34 (s, 2H), 3.26 (d, J=13.5 Hz, 1H), 3.15-3.01(m, 1H), 1.83-1.65 (m, 2H), 1.50-1.15 (m, 16H), 0.87 (t, J=6.7 Hz, 3H).¹³C NMR (101 MHz, DMSO) δ: 175.12, 171.58, 171.13, 167.99, 166.02,162.54, 154.10, 142.44, 131.16, 130.02, 129.89, 127.23, 126.81, 124.91,124.25, 115.50, 115.36, 67.97, 54.23, 40.10, 37.12, 34.57, 31.19, 30.88,28.46, 28.37, 25.36, 22.02, 13.93.

Compound 68 was prepared from Compound 5 using General Procedures 7, and8 sequentially.

Compounds 69 and 70 were prepared from (S,Z)-methyl2-(4-(tert-butyl)benzamido)-3-(4-(N-hydroxycarbamimidoyl)phenyl)propanoateCompound 2 using General Procedures 7, and 8 sequentially.

Compounds 71 and 72 were prepared from Methyl2-amino-2-(4-bromophenyl)acetate hydrochloride using General Procedures7, 1, 2, 5, and 4 sequentially.

Compounds 73 and 74 were prepared from (S)-methyl2-amino-4-(4-hydroxyphenyl)butanoate hydrobromide using GeneralProcedures 7, 9, 1, 2, 5, and 4 sequentially.

Compound 75 was prepared from (S)-methyl3-amino-4-(4-hydroxyphenyl)butanoate hydrochloride using GeneralProcedures 7, 9, 1, 2, 5, and 4 sequentially.

4-(heptyloxy)benzohydrazide

To a stirred solution of 4-(heptyloxy)benzoic acid (679 mg, 2.87 mmol)in THF (5 mL) was added 1,1′-carbonyldiimidazole (559 mg, 3.45 mmol).After stirring at room temperature for 2 h, the solution was added to astirred mixture of hydrazine hydrate (0.729 mL, 5.75 mmol) in THF (2 mL)and stirred a further 2 h. The reaction mixture was poured onto water(20 mL) and stirred for 30 min. The resulting precipitate was collectedby filtration, washed with water (2×10 mL) then acetonitrile (3 mL) toafford 0.54 g (71%) of 4-(heptyloxy)benzohydrazide as a white solid.LCMS-ESI (m/z) calculated for C₁₄H₂₂N₂O₂: 250.3 found 251.0 [M+H]⁺,t_(R)=2.05 min. (Method 4).

(S)-methyl2-(4-(tert-butyl)benzamido)-3-(4-(2-(4-(heptyloxy)benzoyl)hydrazine-carbonyl)phenyl)propanoate(INT-3)

To a stirring solution of(S)-4-(2-(4-(tert-butyl)benzamido)-3-methoxy-3-oxopropyl)benzoic acidINT-1 (260 mg, 0.68 mmol) in THF (5 mL) were added 4-methylmorpholine(0.15 mL, 1.36 mmol) and isobutyl carbonochloridate (0.09 mL, 0.71mmol). After stirring at room temperature for 2 h,4-(heptyloxy)benzohydrazide (187 mg, 0.75 mmol) was added and stirringcontinued for another 2 h. The reaction mixture was poured onto NaHCO₃(50 mL) and extracted with DCM (3×20 mL). The combined organics weredried over MgSO₄ and evaporated. The crude product was purified bycolumn chromatography (100% EA in iso-hexanes) to afford 297 mg (71%) of(S)-methyl2-(4-(tert-butyl)benzamido)-3-(4-(2-(4-(heptyloxy)benzoyl)hydrazinecarbonyl)phenyl)propanoate INT-3 as an off-white foam. LCMS-ESI (m/z) calculated forC₃₆H₄₅N₃O₆: 615.8 found 616.0 [M+H]⁺, t_(R)=2.89 min. (Method 4).

(S)-methyl2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)-1,3,4-oxadiazol-2-yl)phenyl)propanoate

To a stirring solution (S)-methyl2-(4-(tert-butyl)benzamido)-3-(4-(2-(4-(heptyloxy)benzoyl)hydrazinecarbonyl)phenyl)propanoateINT-3 (127 mg, 0.21 mmol) and TEA (0.09 mL, 0.62 mmol) in DCM (4 mL) wasadded 2-chloro-1,3-dimethylimidazolidinium chloride (41.8 mg, 0.25mmol). The reaction mixture was stirred at room temperature for 18 hthen warmed to 40° C. for 1 h. The reaction mixture was cooled to roomtemperature, diluted with NaHCO₃ (15 mL), shaken, split through ahydrophobic frit and evaporated to afford 120 mg (95%) of (S)-methyl2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)-1,3,4-oxadiazol-2-yl)phenyl)propanoateas a white solid. LCMS-ESI (m/z) calculated for C₃₆H₄₃N₃O₅: 597.8; found598.0 [M+H]⁺, t_(R)=3.25 min. (Method 4).

Compound 76 was prepared using (S)-methyl2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)-1,3,4-oxadiazol-2-yl)phenyl)propanoateand General Procedure 4.

2-bromo-1-(4-(heptyloxy)phenyl)ethanone (INT-4)

To a stirring solution of 1-(4-(heptyloxy)phenyl)ethanone (500 mg, 2.13mmol) in THF (8.5 mL) under nitrogen was added phenyltrimethylammoniumtribromide (842 mg, 2.24 mmol). The reaction mixture was stirred at RTfor 2 h, filtered under vacuum and the captured solid washed with THF.The combined liquors were concentrated to afford 919 mg (100%) of2-bromo-1-(4-(heptyloxy)phenyl)ethanone INT-4 as a yellow oil. LCMS-ESI(m/z) calculated for C₁₅H₂₁BrO₂: 313.2; found 313.0 [M+H]⁺, t_(R)=2.12min. (Method 4).

(S)-2-(4-(heptyloxy)phenyl)-2-oxoethyl4-(2-(4-(tert-butyl)benzamido)-3-methoxy-3-oxopropyl)benzoate

A solution of 2-bromo-1-(4-(heptyloxy)phenyl)ethanone, INT-4 (166 mg,0.45 mmol) in acetonitrile (1 mL) was added to a solution of(S)-4-(2-(4-(tert-butyl)benzamido)-3-methoxy-3-oxopropyl)benzoic acidINT-1 (190 mg, 0.50 mmol) and TEA (75.0 μl, 0.54 mmol) in acetonitrile(4 mL). The reaction mixture was stirred at RT for 18 h then poured onto0.5 M citric acid (30 mL) and extracted with EA (3×25 mL). The combinedorganics were dried over MgSO₄, filtered and concentrated. The residuewas triturated with Et₂O (10 mL) and the filtrate concentrated to afford159 mg (49%) of (S)-2-(4-(heptyloxy)phenyl)-2-oxoethyl4-(2-(4-(tert-butyl)benzamido)-3-methoxy-3-oxopropyl)benzoate as a whitesolid. LCMS-ESI (m/z) calculated for C₃₇H₄₅NO₇: 615.8; found 616.0[M+H]⁺, t_(R)=2.76 min. (Method 4).

(S)-methyl2-(4-(tert-butyl)benzamido)-3-(4-(4-(4-(heptyloxy)phenyl)oxazol-2-yl)phenyl)propanoate

To borontrifluoride diethyl etherate (33.3 μl, 0.27 mmol) was added amixture of acetamide (763 mg, 12.9 mmol) and(S)-2-(4-(heptyloxy)phenyl)-2-oxoethyl4-(2-(4-(tert-butyl)benzamido)-3-methoxy-3-oxopropyl)benzoate (159 mg,0.26 mmol). The reaction mixture was stirred at 140° C. for 1 h. Thereaction mixture was allowed to cool to RT, diluted with EA (15 mL) andextracted with NaHCO₃ (3×15 mL) and brine (15 mL). The combined organicswere dried over MgSO₄, filtered and concentrated. The residue wasrecrystallised from Et₂O (5 mL), filtered and rinsed with Et₂O. Thefiltrate was concentrated to afford 55 mg (16%) of (S)-methyl2-(4-(tert-butyl)benzamido)-3-(4-(4-(4-(heptyloxy)phenyl)oxazol-2-yl)phenyl)propanoateas an orange oil. LCMS-ESI (m/z) calculated for C₃₇H₄₄N₂O₅: 596.8; found597.0 [M+H]⁺, t_(R)=3.11 min. (Method 4).

Compound 77 was prepared from (S)-methyl2-(4-(tert-butyl)benzamido)-3-(4-(4-(4-(heptyloxy)phenyl)oxazol-2-yl)phenyl)propanoateusing General Procedure 4.

2-(4-bromophenyl)-2-oxoethyl 4-(heptyloxy)benzoate

To stirring mixture of 4-(heptyloxy)benzoic acid (2.0 g, 8.46 mmol) inacetonitrile (30 mL) at RT was added TEA (1.24 mL, 8.87 mmol) drop wise.The reaction mixture was stirred at RT for 1 h, poured onto 0.05 Mcitric acid (100 mL) and EA (10 mL) then stirred for 10 min. Theprecipitate was isolated by filtration, washed with water (30 mL) andiso-hexanes (2×10 mL) then dried in air to afford 3.8 g (98%) of2-(4-bromophenyl)-2-oxoethyl 4-(heptyloxy)benzoate. LCMS-ESI (m/z)calculated for C₂₂H₂₅BrO₄: 433.3; found 455.0/457.0 [M+Na]⁺, t_(R)=3.21min. (Method 4).

4-(4-bromophenyl)-2-(4-(heptyloxy)phenyl)oxazole

To boron trifluoride etherate (0.322 mL, 2.5 mmol) was added2-(4-bromophenyl)-2-oxoethyl 4-(heptyloxy)benzoate (1.0 g, 2.3 mmol) andacetamide (4.91 g, 83.0 mmol) in DCM (10 mL). The reaction mixture washeated to 50° C. then 140° C. for 16 h, DCM was distilled off. Thereaction mixture was cooled, diluted with acetonitrile and stirred at RTfor 1 h. The precipitate was isolated by filtration to afford 273 mg(23%) of 4-(4-bromophenyl)-2-(4-(heptyloxy)phenyl)oxazole as a brownsolid. LCMS-ESI (m/z) calculated for C₂₂H₂₄BrNO₂: 414.3; found 414.0[M+H]⁺, t_(R)=3.00 min. (Method 4).

(S)-methyl2-((tert-butoxycarbonyl)amino)-3-(4-(2-(4-(heptyloxy)phenyl)oxazol-4-yl)phenyl)propanoate

To zinc (104 mg, 1.59 mmol) stirring in DMF (1.5 mL) was added iodine(20.2 mg, 0.08 mmol). After the color disappeared, (R)-methyl2-((tert-butoxycarbonyl)amino)-3-iodopropanoate (175 mg, 0.53 mmol) andfurther iodine (20.2 mg, 0.08 mmol) were added. After 30 min, themixture was de-gassed by bubbling through N₂ then treated with4-(4-bromophenyl)-2-(4-(heptyloxy)phenyl)oxazole (220 mg, 0.53 mmol),Pd₂dba₃ (12.2 mg, 0.01 mmol) anddicyclohexyl(2′,6′-dimethoxy-[1,1′-biphenyl]-2-yl)phosphine (10.9 mg,0.03 mmol) followed by THF (1 mL). The reaction mixture was heated to50° C. for 2 h, cooled to RT and purified by column chromatography(gradient of 15-95% EA in iso-hexanes) to afford 188 mg (65%) of(S)-methyl2-((tert-butoxycarbonyl)amino)-3-(4-(2-(4-(heptyloxy)phenyl)oxazol-4-yl)phenyl)propanoate.LCMS-ESI (m/z) calculated for C₃₁H₄₀N₂O₆: 536.6; found 537.0 [M+H]⁺,t_(R)=3.72 min. (Method 11).

Compound 78 was prepared from (S)-methyl2-((tert-butoxycarbonyl)amino)-3-(4-(2-(4-(heptyloxy)phenyl)oxazol-4-yl)phenyl)propanoateand 4-(tert-butyl)benzoic acid using General Procedures 8, 7 then 4.

2-(4-bromophenyl)-4-(4-(heptyloxy)phenyl)thiazole

To a stirring solution of 2-bromo-1-(4-(heptyloxy)phenyl)ethanone INT-4(1.37 g, 4.38 mmol) in EtOH (10 mL) were added 4-bromobenzothioamide(0.95 g, 4.38 mmol) and isopropanol (10 mL). The reaction mixture wasstirred at RT for 16 h. The solid was isolated by filtration, washedwith EtOH (5 mL) then taken up in DCM (10 mL) and NaHCO₃ (20 mL) andstirred for 1 h at RT. The solid was isolated by filtration, washed withwater (2×10 mL) and acetonitrile (2×4 mL) then dried to afford 1.02 g(52%) of 2-(4-bromophenyl)-4-(4-(heptyloxy)phenyl)thiazole as a whitemicro-crystalline solid. LCMS-ESI (m/z) calculated for C₂₂H₂₄BrNO_(S):429.1; found 430.0 [M+H]⁺, t_(R)=3.20 min. (Method 4).

(S)-methyl2-((tert-butoxycarbonyl)amino)-3-(4-(4-(4-(heptyloxy)phenyl)thiazol-2-yl)phenyl)propanoate

To a stirring suspension of zinc (228 mg, 3.49 mmol) in DMF (2 mL) wasadded diiodine (44 mg, 0.17 mmol). When the color was discharged,(R)-methyl 2-((tert-butoxycarbonyl)amino)-3-iodopropanoate (382 mg, 1.16mmol) and further diiodine (44.2 mg, 0.17 mmol) were added. Afterstirring at RT for 30 min, the reaction mixture was de-gassed bybubbling through N₂ then2-(4-bromophenyl)-4-(4-(heptyloxy)phenyl)thiazole (500 mg, 1.16 mmol),dicyclohexyl(2′,6′-dimethoxy-[1,1′-biphenyl]-2-yl)phosphine (23.8 mg,0.06 mmol), Pd₂dba₃ (26 mg, 0.03 mmol) and DMF (2 mL) were added. Thereaction mixture was heated to 50° C. for 3 h, cooled and purified bycolumn chromatography (10-80% EA in iso-hexanes) to afford 620 mg (96%)of (S)-methyl2-((tert-butoxycarbonyl)amino)-3-(4-(4-(4-(heptyloxy)phenyl)thiazol-2-yl)phenylpropanoate. LCMS-ESI (m/z) calculated for C₃₁H₄₀N₂O₅S: 552.3; no ionobserved, t_(R)=3.37 min. (Method 4).

Compound 79 was prepared from (S)-methyl2-((tert-butoxycarbonyl)amino)-3-(4-(4-(4-(heptyloxy)phenyl)thiazol-2-yl)phenylpropanoate and 4-(tert-butyl)benzoic acid using General Procedures 8, 7then 4.

4-(heptyloxy)benzothioamide

To stirring suspension of 4-(heptyloxy)benzamide (1.24 g, 5.29 mmol) inDME (20 mL) and THF (10 mL) was added2,4-bis(4-phenoxyphenyl)-1,3,2,4-dithiadiphosphetane 2,4-disulfide (2.80g, 5.29 mmol). The reaction mixture was stirred at RT for 16 h. Thereaction mixture was concentrated onto silica and purified by columnchromatography (0-60% EA in iso-hexanes) to afford 1.4 g (62%) of4-(heptyloxy)benzothioamide as a yellow waxy solid. LCMS-ESI (m/z)calculated for C₁₄H₂₁NOS: 251.4; found 252.0 [M+H]⁺, t_(R)=3.13 min.(Method 6).

4-(4-bromophenyl)-2-(4-(heptyloxy)phenyl)thiazole

To a stirring mixture of 4-(heptyloxy)benzothioamide (1.30 g, 5.17 mmol)in isopropanol (20 mL) was added 2-bromo-1-(4-bromophenyl)ethanone (1.44g, 5.17 mmol). The precipitate was collected by filtration and washedwith EtOH (2×5 mL). The filter cake was slurried with NaHCO₃ (2×20 mL),water (2×20 mL) then EtOH (2×5 mL) and dried to afford 926 mg (41%) of4-(4-bromophenyl)-2-(4-(heptyloxy)phenyl)thiazole as a pale yellowpowder. LCMS-ESI (m/z) calculated for C₂₂H₂₄BrNOS: 429.1; found 430.0[M+H]⁺, t_(R)=3.41 min. (Method 4).

(S)-methyl2-((tert-butoxycarbonyl)amino)-3-(4-(2-(4-(heptyloxy)phenyl)thiazol-4-yl)phenyl)propanoate

To a stirring mixture of zinc (182 mg, 2.79 mmol) in DMF (2 mL) wasadded diiodine (35.4 mg, 0.14 mmol). When the color was discharged,further diiodine (35.4 mg, 0.14 mmol) and (R)-methyl2-((tert-butoxycarbonyl)amino)-3-iodopropanoate (306 mg, 0.93 mmol) wereadded. After 30 min, DMF (1 mL) was added and the mixture de-gassed bybubbling through N₂. To the reaction mixture were added4-(4-bromophenyl)-2-(4-(heptyloxy)phenyl)thiazole (400 mg, 0.93 mmol),Pd₂dba₃ (21 mg, 0.02 mmol) anddicyclohexyl(2′,6′-dimethoxy-[1,1′-biphenyl]-2-yl)phosphine (19 mg, 0.05mmol), the mixture was further de-gassed then heated to 50° C. for 3 h.The reaction mixture was cooled and purified by column chromatography(10-80% EA in iso-hexanes). The product obtained was taken into DCM (4mL) and washed with water (20 mL) and dried through a hydrophobic frit.The organics were suspended in ACN (4 mL) and concentrated to afford 432mg (83%) of (S)-methyl2-((tert-butoxycarbonyl)amino)-3-(4-(2-(4-(heptyloxy)phenyl)thiazol-4-yl)phenyl)propanoateas a yellow foam. LCMS-ESI (m/z) calculated for C₃₁H₄₀N₂O₅S: 552.7; noion observed, t_(R)=3.36 min. (Method 4).

Compound 80 was prepared from (S)-methyl2-((tert-butoxycarbonyl)amino)-3-(4-(2-(4-(heptyloxy)phenyl)thiazol-4-yl)phenyl)propanoateand 4-(tert-butyl)benzoic acid using General Procedures 8, 7 then 4.

4-(5-(4-(heptyloxy)phenyl)thiazol-2-yl)benzaldehyde

To a stirring suspension of 4-(thiazol-2-yl)benzaldehyde (349 mg, 1.84mmol), tricyclohexylphosphine (27 mg, 0.07 mmol), pivalic acid (64.2 μl,0.55 mmol), potassium carbonate (382 mg, 2.77 mmol) and palladium (II)acetate (8 mg, 0.04 mmol) in DMA (5.15 mL) under nitrogen was added asolution of 1-bromo-4-(heptyloxy)benzene (500 mg, 1.84 mmol) in DMA (1mL). The reaction mixture was evacuated and purged with nitrogen 3 timesthen heated at 100° C. for 6 h. Once cooled, the reaction mixture wasdiluted with EA (40 mL), washed with water (3×40 mL) and brine (40 mL).The organic phase was dried over MgSO₄, filtered and concentrated invacuo to afford a brown-green solid. The crude product was purified bychromatography (0-50% EA in hexanes) to afford 270 mg (37%) of4-(5-(4-(heptyloxy)phenyl)thiazol-2-yl)benzaldehyde as an iridescentyellow solid. LCMS-ESI (m/z) calculated for C₂₃H₂₅NO₂S: 379.5; found380.0 [M+H]⁺, t_(R)=2.99 min. (Method 8).

Methyl2-((tert-butoxycarbonyl)amino)-3-(4-(5-(4-(heptyloxy)phenyl)thiazol-2-yl)phenyl)acrylate

A stirring mixture of 1,1,3,3-tetramethylguanidine (86 μl, 0.69 mmol)was added to a suspension of4-(5-(4-(heptyloxy)phenyl)thiazol-2-yl)benzaldehyde (260 mg, 0.685 mmol)and methyl 2-((tert-butoxycarbonyl)amino)-2-(dimethoxyphosphoryl)acetate(185 mg, 0.62 mmol) in anhydrous THF (10 mL) under nitrogen, at −70° C.The reaction mixture was stirred at −70° C. for 1 h then at RT for 18 h.The reaction mixture was diluted with DCM (50 mL), washed with water (50mL), passed through a phase separation cartridge and the organic phaseconcentrated in vacuo to afford a yellow solid. The solid was trituratedwith EA/EtOH (20 mL) and the collected solid washed with EtOH (10 mL)and Et₂O to afford 284 mg (79%) of methyl2-((tert-butoxycarbonyl)amino)-3-(4-(5-(4-(heptyloxy)phenyl)thiazol-2-yl)phenyl)acrylate as a yellow solid. LCMS-ESI (m/z) calculated for C₃₁H₃₈N₂O₅S:550.7; found 551.0 [M+H]⁺, t_(R)=3.11 min. (Method 8).

Methyl2-((tert-butoxycarbonyl)amino)-3-(4-(5-(4-(heptyloxy)phenyl)thiazol-2-yl)phenyl)propanoate

A stirring mixture of Methyl2-((tert-butoxycarbonyl)amino)-3-(4-(5-(4-(heptyloxy)phenyl)thiazol-2-yl)phenyl)acrylate(50 mg, 0.091 mmol) dissolved in dioxane (5 mL) was hydrogenated usingan H-Cube hydrogenator (10% Pd/C, 30×4 mm, full hydrogen, 40° C., 1mL/min). The reaction mixture was concentrated in vacuo to afford 21 mg(29%) of methyl2-((tert-butoxycarbonyl)amino)-3-(4-(5-(4-(heptyloxy)phenyl)thiazol-2-yl)phenyl) propanoate as a yellow solid. LCMS-ESI (m/z)calculated for C₃₁H₄₀N₂O₅S: 552.7; found 553.0 [M+H]⁺, t_(R)=1.85 min.(Method 8).

Compound 81 was prepared from Methyl2-((tert-butoxycarbonyl)amino)-3-(4-(5-(4-(heptyloxy)phenyl)thiazol-2-yl)phenyl)propanoate and 4-(tert-butyl)benzoyl chloride using General Procedures8, 3 then 4.

Compound 82 was prepared in a similar fashion to Compound 81 using4-(2-(4-(heptyloxy)phenyl)thiazol-5-yl)benzaldehyde in place of44544-(heptyloxy)phenyl)thiazol-2-yl)benzaldehyde.

(S)-methyl2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)-1,3,4-thiadiazol-2-yl)phenyl)propanoate

Prepared using INT-3: To a stirring solution of2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane 2,4-disulfide (65.7mg, 0.16 mmol) in THF (3 mL) was added (S)-methyl2-(4-(tert-butyl)benzamido)-3-(4-(2-(4-(heptyloxy)benzoyl)hydrazinecarbonyl)phenyl)propanoateINT-3 (100.0 mg, 0.16 mmol) and the mixture heated to 65° C. After 1 h,the reaction mixture was concentrated and purified by columnchromatography (10-100% EA in iso-hexanes) to afford 37.0 mg (29%) of(S)-methyl2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)-1,3,4-thiadiazol-2-yl)phenyl)propanoateas a yellow solid. LCMS-ESI (m/z) calculated for C₃₆H₄₃N₃O₄S: 613.8; noion observed, t_(R)=3.31 min. (Method 4).

Compound 83 was prepared from (S)-methyl2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)-1,3,4-thiadiazol-2-yl)phenyl)propanoateusing General Procedure 4.

Compound 84 was prepared using 3-bromo-5-chloro-1,2,4-thiadiazole,(4-(heptyloxy)phenyl)boronic acid and INT-13 using General Procedures10, 10, and 8 sequentially.

(S)-tert-butyl2-(((benzyloxy)carbonyl)amino)-3-(4-(((trifluoromethyl)sulfonyl)oxy)-phenyl)propanoate (INT-5)

Prepared using General Procedure 9: A stirred solution of (S)-tert-butyl2-(((benzyloxy)carbonyl)amino)-3-(4-hydroxyphenyl)propanoate hydrate (25g, 64.2 mmol) in DCM (100 mL) was treated with magnesium sulfate (4.01g, 33.7 mmol). After 15 min, the mixture was filtered and washed withDCM (2×20 mL). The organics were treated withN-ethyl-N-isopropylpropan-2-amine (17.41 g, 134.7 mmol) and stirred.This solution was treated with1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide(26.44 g, 74.01 mmol) and the mixture was allowed to stir overnight atRT. The mixture was treated with water (50 mL) and saturated aqueousNaHCO₃ (20 mL) and stirred vigorously for 10 min. The layers wereseparated and the organic layer was further washed with saturatedaqueous NaHCO₃ (2×50 mL), water (50 mL), and saturated aqueous NaHCO₃(50 mL) and concentrated. The compound was purified by chromatography(EA/hexanes) to afford 26.85 g (79%) of (S)-tert-butyl2-(((benzyloxy)carbonyl)amino)-3-(4-(((trifluoromethyl)sulfonyl)oxy)phenyl)propanoateINT-5. LCMS-ESI (m/z) calculated for C₂₂H₂₄F₃NO₇S: 503.1; found 526.1[M+Na]⁺, t_(R)=4.12 min (Method 3).

(S)-tert-butyl2-(((benzyloxy)carbonyl)amino)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoate(INT-6)

A solution of (S)-tert-butyl 2-(((benzyloxy)carbonyl)amino)-3-(4-(((trifluoromethyl)sulfonyl)oxy)phenyl)propanoateINT-5 (26.85 g, 53.4 mmol), potassium acetate (15.71 g, 160.1 mmol),bis-pinacolatoborane (27.1 g, 106.7 mmol) and DMSO (100 mL) was degassedwith a steady flow of nitrogen gas for 5 minutes. To this solution wasadded PdCl₂(dppf) (1.95 g, 2.67 mmol) and the solution further degassedand kept under an atmosphere of nitrogen. The mixture was heated at 100°C. for 18 h then cooled to RT and diluted with EA (50 mL) and washedwith saturated aqueous NaHCO₃ (20 mL), water (3×30 mL), dried overMgSO₄, filtered, and the solvent removed under reduced pressure. Thecompound was purified by column chromatography to give 11.10 g (41%) of(S)-tert-butyl2-(((benzyloxy)carbonyl)amino)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoateINT-6 as a oil. LCMS-ESI (m/z) calculated for C₂₇H₃₆BNO₆: 481.3; found504.3 [M+Na]′, t_(R)=4.21 min (Method 3). ¹H NMR (400 MHz, DMSO) δ 7.72(d, J=8.3 Hz, 1H), 7.60 (d, J=8.0 Hz, 2H), 7.42-7.11 (m, 6H), 4.98 (s,2H), 4.22-4.08 (m, 1H), 3.03 (dd, J=13.7, 5.2 Hz, 1H), 2.85 (dd, J=13.6,10.1 Hz, 1H), 1.36 (s, 6H), 1.30 (s, 9H), 1.22-1.13 (m, 6H).

(S)-tert-butyl2-(((benzyloxy)carbonyl)amino)-3-(4-(5-bromopyrimidin-2-yl)phenyl)propanoate (INT-7)

Prepared using General Procedure 10: A stirred mixture of (S)-tert-butyl2-(((benzyloxy)carbonyl)amino)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoate INT-6 (21.7 g, 45.0 mmol) and 5-bromo-2-iodopyrimidine (15.4g, 54.0 mmol) in dioxane (400 mL) with sodium carbonate decahydrate(25.7 g, 90 mmol) in water (100 mL) was de-gassed. PdCl₂(dppf) (0.99 g,1.4 mmol) was added and the mixture further de-gassed then heated toreflux for 5 h. The mixture was allowed to cool while stirringovernight. The mixture was poured onto water (1 L) and EA (300 mL) andstirred for 30 min. The mixture was filtered and the layers wereseparated. The aqueous layer was further extracted with EA (2×200 mL)and the combined organic layers were washed with water (2×100 mL) thenbrine (50 mL), dried over MgSO₄ and concentrated. Column chromatography(EA/hexanes) gave 14.84 g (63%) of (S)-tert-butyl2-(((benzyloxy)carbonyl)amino)-3-(4-(5-bromopyrimidin-2-yl)phenyl)propanoateINT-7. LCMS-ESI (m/z) calculated for C₂₅H₂₆BrN₃O₄: 511.1; found 534.0[M+Na], t_(R)=2.97 min (Method 11).

(S)-tert-butyl2-(((benzyloxy)carbonyl)amino)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoate(INT-8)

Prepared using General Procedure 10: A stirred solution of(S)-tert-butyl2-(((benzyloxy)carbonyl)amino)-3-(4-(5-bromopyrimidin-2-yl)phenyl)propanoateINT-7 (759 mg, 1.48 mmol), (4-(heptyloxy)phenyl)boronic acid (455 mg,1.93 mmol) and sodium bicarbonate (311 mg, 3.70 mmol) in acetonitrile (5ml), THF (5 ml), and water (4 ml) was degassed with N₂ for 5 min.Pd(dppf)Cl₂ (108 mg, 0.15 mmol) was added and the reaction was heated to110° C. in the microwave for 50 min. The reaction was diluted with EAand water then filtered. The organic phase was dried over MgSO₄,filtered, and concentrated. The crude product was purified bychromatography on silica gel (EA/hexanes) to afford 591 mg (62%) of(S)-tert-butyl2-(((benzyloxy)carbonyl)amino)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoateINT-8 as a yellow solid. LCMS-ESI (m/z) calculated for C₃₈H₄₅N₃O₅:623.8; no m/z observed, t_(R)=3.42 min (Method 8).

(S)-tert-butyl2-amino-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoate(INT-9)

To a stirred solution of (S)-tert-butyl2-(((benzyloxy)carbonyl)amino)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoateINT-8 (591 mg, 0.95 mmol) in EA (25 ml) was added Pd/C (101 mg, 0.09mmol) and the suspension degassed with H₂. The mixture was stirredvigorously under an atmosphere of H₂ overnight then filtered throughcelite and the filtrate was concentrated to give 405 mg (83%) of(S)-tert-butyl2-amino-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoateINT-9. LCMS-ESI (m/z) calculated for C₃₀H₃₉N₃O₃: 489.3; found: 490.2[M+H]⁺, t_(R)=2.35 min (Method 8).

(S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoicacid (Compound 85)

A stirred solution of (S)-tert-butyl2-amino-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoateINT-9 (1.34 g, 2.74 mmol) and 4-(tert-butyl)benzoic acid (0.54 g, 3.01mmol) in DMF (5 mL) and N-ethyl-N-isopropylpropan-2-amine (1.01 ml, 5.47mmol) was treated with HATU (1.09 g, 2.87 mmol). After stirring for 1 h,the mixture was treated with water (60 mL) and iso-hexanes (20 mL) andstirred for 1 h. The product was collected by filtration, washed withwater (3×10 mL) then iso-hexanes (10 mL) and dried in the vacuum oven.The ester was taken up in DCM (5 mL) and treated with TFA (5 mL). After2 h, the mixture was treated with toluene (5 mL) and evaporated. Theresidue was taken up in DMSO (6 mL) then treated with water (20 mL) andstirred for 1 h. The product was collected by filtration, washed withwater (3×15 mL) then acetonitrile (2×5 mL), and dried in the vacuum ovento give 1.40 g (85%) of(S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoic acid Compound 85 as a white solid.LCMS-ESI (m/z) calculated for C₃₇H₄₃N₃O₄: 593.3; found: 594.0 [M+H]⁺,t_(R)=11.18 min (Method 9) and 97% e.e. (Chiral Method). ¹H NMR (400MHz, DMSO-d6) δ 12.79 (br, s, 1H), 9.16 (s, 2H), 8.66 (d, J=8.2 Hz, 1H),8.45-8.27 (m, 2H), 7.89-7.69 (m, 4H), 7.57-7.38 (m, 4H), 7.18-7.02 (m,2H), 4.77-4.62 (m, 1H), 4.03 (t, J=6.5 Hz, 2H), 3.30-3.24 (m, 1H),3.22-3.12 (m, 1H), 1.80-1.68 (m, 2H), 1.48-1.20 (m, 17H), 0.96-0.82 (m,3H).

Compounds 86-102, 104-158 and 296 were prepared from (S)-tert-butyl2-amino-3-(4-(5-(4-(heptyloxy)phenyl) pyrimidin-2-yl)phenyl)propanoateINT-8 using General Procedures 3 or 7 followed by 4 or 8.

(S)-tert-butyl2-(((benzyloxy)carbonyl)amino)-3-(4-(5-(4-(tert-butyl)phenyl)pyrimidin-2-yl)phenyl)propanoate (INT-10)

Prepared using General Procedure 10: A stirred solution of(S)-tert-butyl2-(((benzyloxy)carbonyl)amino)-3-(4-(5-bromopyrimidin-2-yl)phenyl)propanoateINT-7 (0.96 g, 1.86 mmol), (4-(tert-butyl)phenyl)boronic acid (0.43 g,2.42 mmol) and sodium bicarbonate (0.39 g, 4.66 mmol) in acetonitrile (5ml), THF (5 ml) and water (5 ml) was degassed with N₂ for 5 min.Pd(dppf)Cl₂ (0.136 g, 0.186 mmol) was added and the reaction was heatedto 110° C. in the microwave for 45 min. The reaction was diluted with EA(50 mL) and filtered over celite. The organic phase was washed withwater (100 mL) and concentrated. The crude product was purified bychromatography on silica gel (EA/isohexanes) to afford 757 mg (70%) of(S)-tert-butyl2-(((benzyloxy)carbonyl)amino)-3-(4-(5-(4-(tert-butyl)phenyl)pyrimidin-2-yl)phenyl)propanoateINT-10 as a white powder. LCMS-ESI (m/z) calculated for C₃₅H₃₉N₃O₄:565.3; no m/z observed, t_(R)=3.39 min (Method 8).

(S)-tert-butyl2-amino-3-(4-(5-(4-(tert-butyl)phenyl)pyrimidin-2-yl)phenyl)-propanoate(INT-11)

To a stirred solution of (S)-tert-butyl2-(((benzyloxy)carbonyl)amino)-3-(4-(5-(4-(tert-butyl)phenyl)pyrimidin-2-yl)phenyl)propanoateINT-10 (757 mg, 1.34 mmol) in EA (100 ml) was added Pd/C (142 mg, 0.13mmol) and the suspension degassed with H₂. The mixture was stirredvigorously under an atmosphere of H₂ overnight then filtered throughcelite and the filtrate was concentrated to give 532 mg (88%) of(S)-tert-butyl2-amino-3-(4-(5-(4-(tert-butyl)phenyl)pyrimidin-2-yl)phenyl)propanoateINT-11. LCMS-ESI (m/z) calculated for C₂₇H₃₃N₃O₂: 431.3; found: 432.0[M+H]⁺, t_(R)=2.01 min (Method 4).

Compounds 159-181 were prepared from (S)-tert-butyl2-amino-3-(4-(5-(4-(tert-butyl)phenyl)pyrimidin-2-yl)phenyl)propanoateINT-11 using General Procedures 3 or 7 followed by 4 or 8.

Compound 182 can be prepared in a manner analogous to 165 starting from(R)-tert-butyl2-(((benzyloxy)carbonyl)amino)-3-(4-hydroxyphenyl)propanoate.

Compound 183 was prepared from(S)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)-2-(4-hydroxybenzamido)propanoicacid, Compound 114 using General Procedure 13.

Compounds 184-190 were prepared from (S)-tert-butyl2-amino-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoateINT-9 using General Procedures 13 and 8 sequentially.

Compound 191 can be prepared in a manner analogous to 85 starting from(R)-tert-butyl2-(((benzyloxy)carbonyl)amino)-3-(4-hydroxyphenyl)propanoate.

(S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(heptyloxy)phenyl)-pyrimidin-2-yl)phenyl)propanoicacid (Compound 192)

A stirring solution of (S)-tert-butyl2-amino-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoateINT-9 (5.50 g, 11.23 mmol) and 5-(tert-butyl)thiophene-2-carboxylic acid(2.13 g, 11.57 mmol) in DMF (50 mL) and DIEA (6.22 ml, 33.70 mmol) wastreated portion wise with HATU (4.48 g, 11.79 mmol). After stirring for1 h, the mixture was treated with water (200 mL) and iso-hexanes (20 mL)and stirred for 10 min. The product was collected by filtration, washedwith iso-hexanes (2×30 mL), water (2×50 mL) then MeOH (20 mL) andiso-hexanes (30 mL). The ester was taken up in DCM (50 mL) and treatedwith TFA (10 mL). After 1 h, additional TFA (15 mL) was added. After afurther 5 h, the mixture was treated with toluene (20 mL) andconcentrated. The residue was washed with acetonitrile (25 mL) thentaken up in DMSO (20 mL) then treated with water (100 mL) and stirredfor 1 h. The product was collected by filtration, washed with water(4×50 mL) then acetonitrile (3×30 mL), and dried in a vacuum oven togive 5.30 g (75%) of(S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoic acid, Compound 192 as an off-whitesolid. LCMS-ESI (m/z) calculated for C₃₅H₄₁N₃O₄S: 599.3; no m/zobserved, t_(R)=11.10 min (Method 10). The chiral purity was 98% e.e.(Chiral Method). ¹H NMR (400 MHz, DMSO-d6) δ 12.87 (s, 1H), 9.17 (s,2H), 8.68 (d, J=8.3 Hz, 1H), 8.47-8.17 (m, 2H), 7.96-7.71 (m, 2H), 7.64(d, J=3.8 Hz, 1H), 7.55-7.29 (m, 2H), 7.26-7.02 (m, 2H), 6.93 (d, J=3.8Hz, 1H), 4.79-4.48 (m, 1H), 4.03 (t, J=6.5 Hz, 2H), 3.27 (dd, J=13.9,4.5 Hz, 1H), 3.12 (dd, J=13.9, 10.6 Hz, 1H), 1.90-1.58 (m, 2H),1.58-1.01 (m, 17H), 1.01-0.69 (m, 3H).

Compound 193 was be prepared in a manner analogous to 192 starting from(R)-tert-butyl2-(((benzyloxy)carbonyl)amino)-3-(4-hydroxyphenyl)propanoate.

Tert-butyl (4-(tert-butyl)benzoyl)-L-tyrosinate

Prepared using General Procedure 7. Into a solution of4-(tert-butyl)benzoic acid (8.3 g, 46.4 mmol) in DMF (100 mL) were addedHATU (19.2 g, 50.6 mmol), TEA (17.6 mL, 126.4 mmol) and (S)-tert-butyl2-amino-3-(4-hydroxyphenyl)propanoate (10.0 g, 42.1 mmol). After 5 h,the reaction mixture was diluted with EA, washed with saturated aqueousNaHCO₃ and brine, then dried (Na₂SO₄), concentrated, and purified bychromatography (EA/hexanes) to provide 12.9 g (69%) of tert-butyl(4-(tert-butyl)benzoyl)-L-tyrosinate. LCMS-ESI (m/z) calculated forC₂₄H₃₁NO₄: 397.5; no m/z observed, t_(R)=3.59 min (Method 1). ¹H NMR(400 MHz, CDCl₃) δ 7.71-7.65 (m, 2H), 7.47-7.39 (m, 2H), 7.04 (t, J=5.7Hz, 2H), 6.78-6.70 (m, 2H), 6.59 (d, J=7.5 Hz, 1H), 4.91 (dt, J=7.5, 5.6Hz, 1H), 3.15 (qd, J=14.0, 5.6 Hz, 2H), 1.45 (s, 9H), 1.33 (s, 9H).

Tert-butyl(S)-2-(4-(tert-butyl)benzamido)-3-(4-(((trifluoromethyl)sulfonyl)oxy)phenylpropanoate(INT-12)

Prepared using General Procedure 9. Into a solution of tert-butyl(4-(tert-butyl)benzoyl)-L-tyrosinate (8.0 g, 17.9 mmol) were added DIEA(3.7 mL, 1.2 mmol) and N-Phenylbis(trifluoromethanesulfonimide) (7.0 g,19.7 mmol). After stirring for 36 h, the reaction mixture was dilutedwith DCM then washed with 10% aqueous citric acid and saturated aqueousNaHCO₃. The organic layer was dried over Na₂SO₄, and concentrated toprovide 9.5 g (100%) tert-butyl(S)-2-(4-(tert-butyl)benzamido)-3-(4-(((trifluoromethyl)sulfonyl)oxy)phenyl)propanoateINT-12, which was used without further purification. LCMS-ESI (m/z)calculated for C₂₅H₃₀F₃NO₆S: 529.6; no m/z observed, t_(R)=4.42 min(Method 1). ¹H NMR (400 MHz, CDCl₃) δ 7.71-7.65 (m, 2H), 7.49-7.43 (m,2H), 7.32-7.26 (m, 2H), 7.22-7.16 (m, 2H), 6.69 (d, J=7.0 Hz, 1H), 4.94(dt, J=6.9, 5.9 Hz, 1H), 3.24 (t, J=7.1 Hz, 2H), 1.41 (s, 9H), 1.33 (s,9H).

Tert-butyl(S)-2-(4-(tert-butyl)benzamido)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoate(INT-13)

Into a degassed solution of(S)-2-(4-(tert-butyl)benzamido)-3-(4-(((trifluoromethyl)sulfonyl)oxy)phenyl)propanoateINT-12 (9.5 g, 24 mmol), KOAc (7.0 g, 72 mmol), and bis-pinacolatoborane(9.1 g, 36 mmol) in DMSO (20 mL) was added Pd(dppf)Cl₂ (0.87 g, 1 mmol).The reaction mixture was heated at 100° C. for 12 h under an atmosphereof N₂. The reaction mixture was diluted with EA then washed withsaturated aqueous NaHCO₃ and H₂O. The organic layer was dried overNa₂SO₄, concentrated, and purified by chromatography (EA/hexanes) toprovide 7.2 g (60%) of tert-butyl(S)-2-(4-(tert-butyl)benzamido)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoate INT-13. LCMS-ESI (m/z) calculated for C₃₀H₄₂BNO₅: 507.5; nom/z observed, t_(R)=4.53 min (Method 1). ¹H NMR (400 MHz, CDCl₃) δ 7.74(d, J=8.0 Hz, 2H), 7.72-7.67 (m, 2H), 7.48-7.43 (m, 2H), 7.21 (d, J=8.0Hz, 2H), 6.59 (d, J=7.4 Hz, 1H), 5.05-4.92 (m, 1H), 3.27 (qd, J=13.7,5.4 Hz, 2H), 1.47 (s, 9H), 1.36 (m, 21H).

Tert-butyl(S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(4-(tert-butyl)benzamido)propanoate(INT-14)

Prepared using General Procedure 10. Into a degassed solution of(S)-2-(4-(tert-butyl)benzamido)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoateINT-13 (1.0 g, 2.0 mmol), Na₂HCO₃ (420 mg, 3.9 mmol), and5-bromo-2-iodopyrimidine (615 mg, 2.2 mmol) in 2/2/1 MeCN/THF/H₂O wasadded Pd(dppf)Cl₂ (140 mg, 0.2 mmol). The reaction mixture was heated at110° C. for 1 h in a microwave reactor. The reaction mixture wasconcentrated, dissolved in DCM and washed with H₂O. The organic layerwas dried over Na₂SO₄, concentrated, and purified by chromatography(EA/hexanes) to provide 630 mg (58%) of tert-butyl(S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(4-(tert-butyl)benzamido)propanoateINT-14. LCMS-ESI (m/z) calculated for C₂₈H₃₂BrN₄O₃: 538.5; no m/zobserved, t_(R)=4.66 min (Method 1). ¹H NMR (400 MHz, CDCl₃) δ 8.84-8.78(s, 2H), 8.31 (t, J=7.0 Hz, 2H), 7.75-7.64 (m, 2H), 7.46-7.38 (m, 2H),7.30 (dd, J=12.9, 7.1 Hz, 2H), 6.65 (d, J=7.2 Hz, 1H), 5.10-4.94 (m,1H), 3.43-3.20 (m, 2H), 1.45 (s, 9H), 1.32 (s, 9H).

Compounds 194-236 were prepared from tert-butyl(S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(4-(tert-butyl)benzamido)propanoateINT-14 using General Procedures 10 and 8 sequentially.

Tert-butyl (5-(tert-butyl)thiophene-2-carbonyl)-L-tyrosinate

Prepared using General Procedure 7. Into a solution of5-(tert-butyl)thiophene-2-carboxylic acid (1.93 g, 10.0 mmol) in DMF (20mL) were added HATU (4.56 g, 12.0 mmol) and TEA (4.18 mL, 30.0 mmol).The mixture was stirred at room temperature for 30 min and(S)-tert-butyl 2-amino-3-(4-hydroxyphenyl)propanoate (2.37 g, 10.0 mmol)was added. After 1 h, the reaction mixture was poured into 400 mL ofice-water and the solid was filtered. The solid was dissolved in DCM andEA, dried over MgSO₄, concentrated, and purified by chromatography(EA/hexanes) to provide 3.6 g (89%) of tert-butyl(5-(tert-butyl)thiophene-2-carbonyl)-L-tyrosinate. LCMS-ESI (m/z)calculated for C₂₂H₂₉NO₄S: 403.2; found: 426.1 [M+Na]⁺, t_(R)=9.07 min(Method 2).

Tert-butyl(S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(((trifluoromethyl)sulfonyl)oxy)phenyl)propanoate(INT-15)

Prepared using General Procedure 9. Into a solution of tert-butyl(5-(tert-butyl)thiophene-2-carbonyl)-L-tyrosinate (3.52 g, 8.72 mmol)were added DIEA (4.56 mL, 26.17 mmol) andN-phenylbis(trifluoromethanesulfonimide) (3.27 g, 9.16 mmol). Afterstirring for 18 h, the reaction mixture was diluted with DCM then washedwith saturated aqueous NaHCO₃. The organic layer was dried over MgSO₄and concentrated. The crude product was purified by chromatography toprovide 4.10 g (87.6%) of tert-butyl(S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(((trifluoromethyl)sulfonyl)oxy)phenyl) propanoate INT-15. LCMS-ESI (m/z) calculated forC₂₃H₂₈F₃NO₆S₂: 535.1; no m/z observed, t_(R)=4.22 min (Method 3).

Tert-butyl(S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoate(INT-16)

Into a degassed solution of tert-butyl(S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(((trifluoromethyl)sulfonyl)oxy)phenyl)propanoateINT-15 (3.89 g, 7.26 mmol), KOAc (2.14 g, 21.79 mmol), andbis-pinacolatoborane (2.40 g, 9.44 mmol) in DMSO (50 mL) was addedPd(dppf)Cl₂ (0.27 g, 0.36 mmol). The reaction mixture was heated at 100°C. for 18 h under an atmosphere of N₂. The reaction mixture was pouredinto 600 mL of ice-water and the solid was filtered. The precipitate wasdiluted with EA, dried over MgSO₄, concentrated, and purified bychromatography (EA/hexanes) to provide 3.68 g (99%) of tert-butyl(S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoateINT-16. LCMS-ESI (m/z) calculated for C₂₈H₄₀BNO₅S: 513.3; no m/zobserved, t_(R)=4.51 min (Method 3).

Tert-butyl(S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-carboxamido)propanoate(INT-17)

Prepared using General Procedure 10. Into a degassed solution oftert-butyl(S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoateINT-16 (510 mg, 1.0 mmol) and 5-bromo-2-iodopyrimidine (570 mg, 2.0mmol) in 2/2/1 MeCN/THF/saturated aqueous NaHCO₃ (10 mL) was addedPd(dppf)Cl₂ (30 mg, 0.4 mmol). The reaction mixture was heated at 120°C. for 1 h in a microwave reactor. The reaction mixture was diluted withwater (100 mL) and EA (50 mL) and filtered over Celite. The aqueouslayer was extracted with EA (3×30 mL) and the combined organic layer wasdried over MgSO₄, concentrated, and purified by chromatography(EA/hexanes) to provide 342 mg (63%) of tert-butyl(S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-carboxamido)propanoateINT-17. LCMS-ESI (m/z) calculated for C₂₆H₃₀BrN₃O₃S: 543.1; found: 488.0[M-tBu+H]⁺, t_(R)=10.95 min (Method 2).

Compounds 237-247 were prepared from tert-butyl(S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-carboxamido)propanoateINT-17 using General Procedures 10 and 8 sequentially.

Tert-butyl(S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-cyanopyrimidin-2-yl)phenyl)-propanoate(INT-18)

Prepared using General Procedure 1. Into a degassed solution of(S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(4-(tert-butyl)benzamido)propanoateINT-14 (100 mg, 0.190 mmol), and Zn(CN)₂ (44 mg, 0.370 mmol) in NMP (5mL) was added Pd(Ph₃)₄ (2 mg, 0.002 mmol). The mixture was heated for 45min at 80° C. in a microwave reactor then partitioned between DCM andH₂O. The organic layer was dried over Na₂SO₄, concentrated, and purifiedby chromatography (EA/hexanes) to provide 75 mg (84%) of tert-butyl(S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-cyanopyrimidin-2-yl)phenyl)propanoateINT-18. LCMS-ESI (m/z) calculated for C₂₉H₃₂N₄O₃: 484.60; no m/zobserved, t_(R)=4.17 min (Method 1). ¹H NMR (400 MHz, CDCl₃) δ 8.97 (s,2H), 8.38 (d, J=7.9 Hz, 2H), 7.67 (d, J=8.0 Hz, 2H), 7.46-7.35 (m, 2H),7.33 (d, J=7.9 Hz, 2H), 6.77 (d, J=6.8 Hz, 1H), 4.96 (d, J=6.1 Hz, 1H),3.27 (dd, J=13.1, 8.0 Hz, 2H), 1.37 (d, J=34.5 Hz, 9H), 1.26 (d, J=21.0Hz, 9H).

Tert-butyl(S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(N-hydroxycarbamimidoyl)-pyrimidin-2-yl)phenyl)propanoate

Prepared using General Procedure 2. A solution of(S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-cyanopyrimidin-2-yl)phenyl)propanoateINT-18 (35 mg, 0.07 mmol), hydroxylamine (25 μL, 0.36 mmol, 50% solutionin H₂O), and NEt₃ (11 μL, 0.08 mmol) in EtOH (5 mL) was heated at 80° C.for 1.5 h. The reaction mixture was concentrated, dissolved in DCM andwashed with H₂O to provide 22 mg of tert-butyl(S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(N-hydroxycarbamimidoyl)pyrimidin-2-yl)phenyl)propanoate. LCMS-ESI (m/z) calculated forC₂₉H₃₅N₅O₄: 517.6; found 462.2 [M-^(t)Bu+H]⁺, t_(R)=3.72 min (Method 1).¹H NMR (400 MHz, CDCl₃) δ 9.19 (s, 2H), 8.42 (d, J=8.2 Hz, 2H), 7.67(dd, J=8.5, 2.1 Hz, 2H), 7.40 (dd, J=9.2, 8.0 Hz, 2H), 7.34 (dd, J=10.3,8.4 Hz, 2H), 6.74 (dd, J=7.1, 4.7 Hz, 1H), 5.00 (q, J=5.6 Hz, 1H), 2.83(d, J=5.3 Hz, 2H), 1.44 (s, 9H), 1.28 (d, J=22.0 Hz, 9H).

Tert-butyl(S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(5-hexyl-1,2,4-oxadiazol-3-yl)pyrimidin-2-yl)phenyl)propanoate(Compound 248)

Prepared using General Procedure 5. A solution of heptanoic acid (7 mg,0.05 mmol), HOBt (12 mg, 0.09 mmol) and EDC (13 mg, 0.09 mmol) washeated at 80° C. for 2 h. The reaction mixture was diluted with EtOAcand washed with NaHCO₃. The organic layer was dried over Na₂SO₄ andconcentrated. The resulting mixture was dissolved in EtOH (2 mL) andheated for 45 min at 80° C. in a microwave reactor. The mixture wasconcentrated and purified by preparatory HPLC to provide 1.5 mg oftert-butyl(S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(5-hexyl-1,2,4-oxadiazol-3-yl)pyrimidin-2-yl)phenyl)propanoate.LCMS-ESI (m/z) calculated for C₃₆H₄₅N₅O₄: 611.8; no m/z observed,t_(R)=5.5 min (Method 1). ¹H NMR (400 MHz, CDCl₃) δ 9.45 (s, 2H), 8.44(d, J=8.3 Hz, 2H), 7.71 (d, J=8.5 Hz, 2H), 7.48 (d, J=8.5 Hz, 2H), 7.38(d, J=8.3 Hz, 2H), 6.80 (d, J=7.3 Hz, 1H), 5.04 (dd, J=12.7, 5.5 Hz,1H), 3.37 (ddd, J=18.9, 13.8, 5.5 Hz, 2H), 3.02 (t, J=7.6 Hz, 2H), 1.92(dt, J=15.3, 7.5 Hz, 2H), 1.49 (s, 9H), 1.44-1.28 (m, 15H), 0.93 (t,J=7.1 Hz, 3H).

(S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(5-hexyl-1,2,4-oxadiazol-3-yl)pyrimidin-2-yl)phenyl)propanoatewas deprotected using General Procedure 8 to provide 1.4 mg (6% overall)of(S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(5-hexyl-1,2,4-oxadiazol-3-yl)pyrimidin-2-yl)phenyl)propanoic acid Compound 248. LCMS-ESI (m/z) calculated for C₃₂H₃₇N₅O₄:555.68; no m/z observed, t_(R)=11.03 min (Method 2). ¹H NMR (400 MHz,CDCl₃) δ 9.41 (s, 2H), 8.47 (d, J=8.2 Hz, 2H), 7.66 (d, J=8.4 Hz, 2H),7.42 (dd, J=15.1, 8.4 Hz, 4H), 6.60 (d, J=6.8 Hz, 1H), 5.21-4.95 (m,1H), 3.43 (ddd, J=20.0, 14.0, 5.6 Hz, 2H), 3.05-2.90 (m, 2H), 1.98-1.76(m, 2H), 1.55-1.22 (m, 15H), 0.91 (t, J=7.0 Hz, 3H).

Tert-butyl(S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-hydroxyphenyl)pyrimidin-2-yl)phenyl)propanoate

Prepared using General Procedure 10. To a degassed solution oftert-butyl(S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-carboxamido)propanoate INT-17 (180 mg, 0.3 mmol), sodium carbonate (70 mg, 0.7 mmol)and 4-hydroxyphenylboronic acid (55 mg, 0.4 mmol) in 5 mL of 2/2/1MeCN/THF/H₂O was added Pd(dppf)Cl₂ (24 mg, 0.03 mmol). The reactionmixture was heated at 110° C. for 45 min in a microwave reactor. Themixture was filtered through celite, concentrated, then dissolved in DCMand washed with H₂O. The organic layer was concentrated and purified byprep HPLC to provide 131 mg (78%) of tert-butyl(S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-hydroxyphenyl)pyrimidin-2-yl)phenyl)propanoate. LCMS-ESI (m/z) calculated forC₃₂H₃₅N₃O₄S: 557.7; no m/z observed, t_(R)=4.08 min (Method 1). ¹H NMR(400 MHz, CDCl₃) δ 8.98 (s, 2H), 8.35 (d, J=8.1 Hz, 2H), 7.49 (d, J=8.6Hz, 2H), 7.40-7.31 (m, 3H), 6.94 (d, J=8.5 Hz, 2H), 6.81 (d, J=3.8 Hz,1H), 6.51 (d, J=7.5 Hz, 1H), 5.00 (dd, J=12.9, 5.8 Hz, 1H), 3.28 (qd,J=13.8, 5.6 Hz, 2H), 1.47 (s, 9H), 1.39 (s, 9H).

(S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(decyloxy)phenyl)-pyrimidin-2-yl)phenyl)propanoicacid (Compound 249)

Prepared using General Procedure 12. To a solution of tert-butyl(S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-hydroxyphenyl)pyrimidin-2-yl)phenyl) propanoate (20 mg, 0.04 mmol) in DMF (0.5 mL)were added 1-bromodecane (8 μL, 0.05 mmol) and K₂CO₃ (8 mg, 0.05 mmol).The reaction mixture was heated at 40° C. for 18 h, then diluted withDCM and washed with H₂O. The organic layer was dried over Na₂SO₄ andconcentrated. The crude material was deprotected using General Procedure8 then purified by preparatory HPLC to provide 3.9 mg (17%) of(S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(decyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoicacid Compound 249. LCMS-ESI (m/z) calculated for C₃₈H₄₇N₃O₄S: 641.9; nom/z observed, t_(R)=13.49 min (Method 2). ¹H NMR (400 MHz, CDCl₃) δ 9.01(s, 2H), 8.36 (d, J=8.1 Hz, 2H), 7.56 (d, J=8.7 Hz, 2H), 7.44 (d, J=8.2Hz, 2H), 7.33 (d, J=3.8 Hz, 1H), 7.03 (d, J=8.8 Hz, 2H), 6.80 (d, J=3.8Hz, 1H), 6.54 (d, J=6.8 Hz, 1H), 5.13 (d, J=6.8 Hz, 1H), 4.01 (t, J=6.6Hz, 2H), 3.44 (d, J=4.9 Hz, 2H), 1.91-1.72 (m, 2H), 1.47 (dd, J=15.0,7.3 Hz, 2H), 1.38 (s, 9H), 1.28 (s, 12H), 0.88 (t, J=6.8 Hz, 3H).

Compounds 250-252 were prepared from tert-butyl(S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-hydroxyphenyl)pyrimidin-2-yl)phenyl) propanoate using General Procedure 12 followed byGeneral Procedure 8.

(S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(tert-butyl)piperidin-1-yl)pyrimidin-2-yl)phenyl)propanoicacid (Compound 253)

Prepared using General Procedure 11. Into a degassed solution of INT-14(50 mg, 0.09 mmol), sodium tert-butoxide (18 mg, 0.19 mmol) and4-tert-butylpiperidine HCl (23 mg, 0.11 mmol) in dioxane (2.5 mL) wereadded Pd₂(dba)₃ (9 mg, 0.01 mmol) and2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (6 mg, 0.015mmol). The reaction mixture was heated for 45 min at 120° C. in amicrowave reactor. The mixture was diluted with EA and washed withNaHCO₃. The organic layer was dried over Na₂SO₄, concentrated, andpurified by preparatory HPLC. The isolated intermediate was deprotectedusing General Procedure 8 to provide 2.9 mg (6%) of(S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(tert-butyl)piperidin-1-yl)pyrimidin-2-yl)phenyl)propanoicacid Compound 253. LCMS-ESI (m/z) calculated for C₃₃H₄₂N₄O₃: 542.7;found 543.3 [M+H]⁺, t_(R)=10.79 min (Purity). ¹H NMR (400 MHz, CDCl₃) δ8.52 (s, 2H), 8.23 (d, J=8.0 Hz, 2H), 7.72 (d, J=8.4 Hz, 2H), 7.44 (dd,J=11.3, 8.4 Hz, 4H), 6.79 (d, J=6.8 Hz, 1H), 5.18 (d, J=6.5 Hz, 1H),3.89 (d, J=11.9 Hz, 2H), 3.47 (d, J=5.2 Hz, 2H), 2.83 (t, J=11.5 Hz,2H), 1.88 (d, J=12.0 Hz, 2H), 1.52-1.37 (m, 2H), 1.34 (s, 9H), 1.24 (dd,J=24.7, 12.8 Hz, 1H), 0.92 (s, 9H).

Compound 254 was prepared from INT-14 using General Procedure 11 thenGeneral Procedure 8.

Tert-butyl(S)-3-(4-(5-(2H-tetrazol-5-yl)pyrimidin-2-yl)phenyl)-2-(4-(tert-butyl)-benzamido)propanoate

Into a solution of tert-butyl(S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-cyanopyrimidin-2-yl)phenyl)propanoateINT-18 (34 mg, 0.07 mmol) in DMF (2 mL) were added NH₄Cl (7.5 mg, 1.4mmol) and NaN₃ (7 mg, 0.1 mmol). The reaction mixture was heated at 100°C. for 3 h then diluted with EA and washed with NaHCO₃. The organiclayer was dried over Na₂SO₄, concentrated, and purified by preparatoryHPLC to provide 4.6 mg (12%) of tert-butyl(S)-3-(4-(5-(2H-tetrazol-5-yl)pyrimidin-2-yl)phenyl)-2-(4-(tert-butyl)benzamido)propanoate.LCMS-ESI (m/z) calculated for C₂₉H₃₃N₇O₃: 527.6; no m/z observed,t_(R)=3.83 min (Method 1). ¹H NMR (400 MHz, CDCl₃) δ 9.35 (s, 2H), 8.42(d, J=8.1 Hz, 2H), 7.75 (d, J=8.4 Hz, 2H), 7.47 (d, J=8.5 Hz, 2H), 7.43(d, J=8.2 Hz, 2H), 7.11 (d, J=7.8 Hz, 1H), 5.13 (dd, J=14.4, 7.1 Hz,1H), 3.28 (ddd, J=21.0, 13.6, 6.7 Hz, 2H), 1.47 (d, J=6.8 Hz, 9H), 1.33(s, 9H).

Compound 255 was prepared from tert-butyl(S)-3-(4-(5-(2H-tetrazol-5-yl)pyrimidin-2-yl)phenyl)-2-(4-(tert-butyl)benzamido)propanoateusing General Procedure 12 then General Procedure 8.

Compound 256 was prepared from INT-14 and5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one usingGeneral Procedures 10, 12 and 8.

Compound 257 was prepared from INT-14 and 6-Hydroxypyridine-3-boronicacid pinacol ester using General Procedures 10, 12 and 8.

Compound 258 was prepared from INT-13 and5-(benzyloxy)-2-chloropyrimidine using General Procedure 10, followed byGeneral Procedure 8.

Compounds 259 and 260 were prepared from INT-14 and the appropriateboronic acid using General Procedures 10 then 8.

Tert-butyl 4-(4-(heptyloxy)phenyl)-3-oxopiperazine-1-carboxylate

To a stirring solution of 1-bromo-4-(heptyloxy)benzene (447 mg, 1.65mmol) in dioxane (5 mL) were added tert-butyl3-oxopiperazine-1-carboxylate (330 mg, 1.65 mmol), copper I iodide (31.4mg, 0.17 mmol), (1R,2R)—N1,N2-dimethylcyclohexane-1,2-diamine (234 mg,1.65 mmol) and potassium carbonate (456 mg, 3.30 mmol). The reactionmixture was heated at 120° C. for 16 h. The reaction mixture was passedthrough a plug of celite, eluted with EA (50 mL). The organics werewashed with ammonium chloride (25 mL), water (25 mL) and brine (25 mL)then dried over MgSO₄ and concentrated to afford 602 mg (89%) oftert-butyl 4-(4-(heptyloxy)phenyl)-3-oxopiperazine-1-carboxylate.LCMS-ESI (m/z) calculated for C₂₂H₃₄N₂O₄: 390.5; found 319.0 [M+H]⁺,t_(R)=2.90 min. (Method 4).

1-(4-(heptyloxy)phenyl)piperazin-2-one

To tert-butyl 4-(4-(heptyloxy)phenyl)-3-oxopiperazine-1-carboxylate (540mg, 1.38 mmol) was added 4M HCl in dioxane (2.07 mL, 8.30 mmol). Thereaction mixture was stirred at room temperature for 2 h. Theprecipitate was filtered, washed with hexane (5 mL) and dried. The crudeproduct was purified by column chromatography (79/20/1 DCM/MeOH/NH₄) toafford 325 mg (80%) of 1-(4-(heptyloxy)phenyl)piperazin-2-one as acolorless solid. LCMS-ESI (m/z) calculated for C₁₇H₂₆N₂O₂: 290.4; found291.0 [M+H]⁺, t_(R)=1.49 min. (Method 4).

Compound 261 was prepared from INT-12 and1-(4-(heptyloxy)phenyl)piperazin-2-one using General Procedures 11 and8.

Compound 262 was prepared in a similar fashion from INT-12 and1-(4-(heptyloxy)phenyl)imidazolidin-2-one using General Procedures 11and 8.

Compound 263 was prepared using (S)-methyl2-amino-3-(4-nitrophenyl)propanoate hydrochloride, 4-(tert-butyl)benzoicacid and 1-(4-(heptyloxy)phenyl)piperidin-4-one using General Procedures7, 14, 15 then 4.

Tert-butyl 4-(4-(heptyloxy)phenyl)-4-hydroxypiperidine-1-carboxylate

To a stirring solution of 1-bromo-4-(heptyloxy)benzene (668 mg, 2.46mmol) in THF (5 mL) at −78° C. was added butyllithium (985 μl, 2.46mmol). After 30 min, a solution of tert-butyl4-oxopiperidine-1-carboxylate (491 mg, 2.46 mmol) in THF (2 mL) wasadded. After 10 min, the cooling bath was removed and the reactionmixture stirred for 16 h. The reaction mixture was poured onto NH₄Cl (50mL) and extracted with Et₂O (3×20 mL). The combined organics were washedwith water (20 mL), dried over MgSO₄ and evaporated. The crude productwas purified by column chromatography (5-70% AcMe in iso-hexanes) toafford 0.4 g (33%) of tert-butyl4-(4-(heptyloxy)phenyl)-4-hydroxypiperidine-1-carboxylate. LCMS-ESI(m/z) calculated for C₂₃H₃₇NO₄: 391.5; found 414.0 [M+Na]⁺, t_(R)=2.24min. (Method 4).

4-(4-(heptyloxy)phenyl)piperidine (INT-19)

To a stirring solution of tert-butyl4-(4-(heptyloxy)phenyl)-4-hydroxypiperidine-1-carboxylate (388 mg, 0.99mmol) and triethylsilane (791 μl, 4.95 mmol) in DCM (2 mL) cooled to−30° C. was slowly added 2,2,2-trifluoroacetic acid (379 μl, 4.95 mmol)in a drop-wise fashion. The reaction mixture was allowed to warm slowlyand stirring continued for 16 h. The reaction mixture was poured ontoice-water/NaOH (50 mL/5 mL, 2 M) and extracted with DCM (3×20 mL). Thecombined organic extracts were washed successively with water (50 mL)and NaHCO₃ (20 mL), dried over MgSO₄ and evaporated to afford 166 mg(58%) of 4-(4-(heptyloxy)phenyl)piperidine INT-19 as a white, waxysolid. LCMS-ESI (m/z) calculated for C₁₈H₂₉N₀: 275.4; found 276.0[M+H]⁺, t_(R)=2.88 min. (Method 11).

Compound 264 was prepared using INT-12 and INT-19 using GeneralProcedures 11 then 8.

Compound 265 was prepared in a similar fashion to 264 using INT-12 and3-(4-(heptyloxy)phenyl)pyrrolidine using General Procedures 11 then 8.

Compound 266 can be prepared using INT-12 and1-([1,1′-biphenyl]-4-yl)piperazine using General Procedures 11 then 8.

Compound 267 was prepared using INT-12, tert-butyl4-(4-hydroxyphenyl)piperazine-1-carboxylate and 1-bromoheptane usingGeneral Procedures 12, 8, 11 then 8.

Compound 268 was prepared using INT-12, tert-butyl1,4-diazepane-1-carboxylate and 1-bromo-4-(heptyloxy)benzene usingGeneral Procedures 11, 8, 11 then 8.

Compound 269 was prepared using 5-bromo-2-iodopyridine, INT-13 and(4-(heptyloxy)phenyl)boronic acid using General Procedures 10, 10, and 8sequentially.

Compound 270 was prepared using 5-bromo-2-iodopyridine,(4-(heptyloxy)phenyl)boronic acid and INT-13 using General Procedures10, 10, and 8 sequentially.

Compound 271 was prepared using 5-bromo-2-iodopyrimidine,(4-(heptyloxy)phenyl)boronic acid and INT-13 using General Procedures10, 10, and 8 sequentially.

Compound 272 was prepared using 2-bromo-5-iodopyrazine,(4-(heptyloxy)phenyl)boronic acid and INT-13 using General Procedures10, 10, and 8 sequentially.

Compound 273 was prepared using 3-chloro-6-iodopyridazine,(4-(heptyloxy)phenyl)boronic acid and INT-13 using General Procedures10, 10, and 8 sequentially.

3-(4-bromophenyl)-6-(4-(heptyloxy)phenyl)-1,2,4-triazine (INT-20)

To a stirring solution of 4-bromobenzohydrazide (1.85 g, 8.62 mmol) inethanol (10 mL) was added acetic acid (1 mL). The reaction mixture wasstirred at 60° C. for 30 min then2-bromo-1-(4-(heptyloxy)phenyl)ethanone (1.35 g, 4.31 mmol) INT-4 andsodium acetate (0.389 g, 4.74 mmol) were added and the mixture heated toreflux for 30 min. The reaction mixture was cooled to RT and theresultant precipitate was filtered and washed with iso-hexanes (20 mL)then dried. The solid was dissolved in NMP and heated to 120° C. for 16h. The crude material was cooled to RT, diluted with Et₂O (4 mL),filtered, triturated with ethanol (3×2 mL), filtered and dried to afford241 mg (13%) of 3-(4-bromophenyl)-6-(4-(heptyloxy)phenyl)-1,2,4-triazineINT-20 as an orange solid. LCMS-ESI (m/z) calculated for C₂₂H₂₄BrN₃O:425.1; found 426.3 [M+H]⁺, t_(R)=3.40 min (Method 8).

Compound 274 was prepared in a similar fashion to 79 using3-(4-bromophenyl)-6-(4-(heptyloxy)phenyl)-1,2,4-triazine INT-20 in placeof 2-(4-bromophenyl)-4-(4-(heptyloxy)phenyl)thiazole.

6-(4-bromophenyl)-3-(4-(heptyloxy)phenyl)-1,2,4-triazine (INT-21)

To a stirring solution of 4-(heptyloxy)benzohydrazide (400 mg, 1.60mmol) in ethanol (15 mL) was added acetic acid (1 mL). The reactionmixture was stirred at 60° C. for 30 min then2-bromo-1-(4-bromophenyl)ethanone (222 mg, 0.80 mmol) and sodium acetate(72.1 mg, 0.88 mmol) were added and the solution heated to reflux for 2h. The reaction mixture was cooled to RT and the resultant crystals werefiltered, washed with iso-hexanes (20 mL) then dried to afford 108 mg(31%) of 6-(4-bromophenyl)-3-(4-(heptyloxy)phenyl)-1,2,4-triazineINT-21. LCMS-ESI (m/z) calculated for C₂₂H₂₄BrN₃O: 425.1; found 426.1[M+H]⁺, t_(R)=3.38 min (Method 8).

Compound 275 was prepared in a similar fashion to 274 using6-(4-bromophenyl)-3-(4-(heptyloxy)phenyl)-1,2,4-triazine INT-21 in placeof 3-(4-bromophenyl)-6-(4-(heptyloxy)phenyl)-1,2,4-triazine.

Compound 276 was prepared using 274 using General Procedures 7 and 8.

Compounds 277 and 278 were prepared using INT-16 and5-bromo-2-iodopyridine using General Procedures 10, 10, and 8sequentially.

Compounds 279 and 280 were prepared using INT-16 and3-chloro-6-iodopyridazine using General Procedures 10, 10, and 8sequentially.

Compounds 281 and 282 were prepared using INT-16 and2-bromo-5-iodopyrazine using General Procedures 10, 10, and 8sequentially.

Compound 283 was prepared from Compound 279 and tert-butyl glycinateusing General Procedures 7 and 8 sequentially.

Compound 284 was prepared from Compound 281 and tert-butyl glycinateusing General Procedures 7 and 8 sequentially.

Compound 285 was prepared from Compound 277 and tert-butyl glycinateusing General Procedures 7 and 8 sequentially.

2-(4-(heptyloxy)phenyl)-2-oxoethyl 4-bromobenzoate

To a solution of 2-bromo-1-(4-(heptyloxy)phenyl)ethanone INT-4 (1.3 g,4.2 mmol) and 4-bromobenzoic acid (0.70 g, 3.5 mmol) in ACN (30 mL) wasadded TEA (0.72 ml, 5.2 mmol). After stirring overnight, the mixture waspoured onto aq. citric acid and EA then stirred for 10 min before thesolid was collected by filtration. The cake was washed with water andiso-hexanes then dried to provide 905 mg (57%) of2-(4-(heptyloxy)phenyl)-2-oxoethyl 4-bromobenzoate. LCMS-ESI (m/z)calculated for C₂₂H₂₅BrO₄: 432.1; found 433.2 [M+H]⁺, t_(R)=3.24 min(Method 8).

2-(4-bromophenyl)-5-(4-(heptyloxy)phenyl)-1H-imidazole

To a solution of 2-(4-(heptyloxy)phenyl)-2-oxoethyl 4-bromobenzoate (905mg, 2.09 mmol) in toluene (6 ml) was added CH₃COONH₄ (1600 mg, 20.9mmol). After heating overnight at 115° C., the reaction mixture wasdiluted with aq. NaHCO₃ and extracted into DCM. The organic layers werecombined, dried over MgSO₄, filtered, and the solvent was removed underreduced pressure. The crude reaction mixture was purified bychromatography (EA/hexanes) to provide 370 mg (33%) of2-(4-bromophenyl)-5-(4-(heptyloxy)phenyl)-1H-imidazole. LCMS-ESI (m/z)calculated for C₂₂H₂₅BrN₂O: 412.1; found 413.2 [M+H]⁺, t_(R)=2.33 min(Method 8).

2-(4-bromophenyl)-5-(4-(heptyloxy)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole

To a solution of 2-(4-bromophenyl)-5-(4-(heptyloxy)phenyl)-1H-imidazole(370 g, 900 mmol) in DMF (4 ml) was added NaH (40 mg, 980 mmol). After 2h, 2-(trimethylsilyl)ethoxymethyl chloride (160 g, 990 mmol) in THF (2ml) was added dropwise and reaction mixture was stirred overnight. Thereaction mixture was diluted with EA and washed with aq. NaHCO₃. Theorganics were dried over MgSO₄, filtered, and the solvent was removedunder reduced pressure. The crude product was purified by chromatography(EA/hexane) to afford 32 mg (65%) of2-(4-bromophenyl)-5-(4-(heptyloxy)phenyl)-1-(2-(trimethylsilyl)ethoxy)methyl)-1H-imidazoleas a tan solid. LCMS-ESI (m/z) calculated for C₂₈H₃₉BrN₂O₂Si: 542.2;found 543.3 [M+H]⁺, t_(R)=3.35 min (Method 8).

(S)-methyl2-((tert-butoxycarbonyl)amino)-3-(4-(4-(4-(heptyloxy)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)phenyl)propanoate

A stirred suspension of zinc (68 mg, 1.03 mmol) in DMF (2 mL) wastreated with I₂ (12 mg, 0.05 mmol). After the color disappeared,((R)-methyl 2-((tert-butoxycarbonyl)amino)-3-iodopropanoate (110 mg,0.34 mmol) and further I₂ (12 mg, 0.05 mmol) were added. After 30 min,the mixture was de-gassed then2-(4-bromophenyl)-5-(4-(heptyloxy)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole (170 mg, 0.31 mmol),dicyclohexyl(2′,6′-dimethoxy-[1,1′-biphenyl]-2-yl)phosphine (7 mg, 0.02mmol) and Pd₂(dba)₃ (8 mg, 7.8 μmol) were added. After furtherde-gassing, DMF (2 mL) was added and the reaction mixture was heated at50° C. overnight. The reaction mixture purified by column chromatography(EA/hexane) to provide 55 mg (25%) of (S)-methyl2-((tert-butoxycarbonyl)amino)-3-(4-(4-(4-(heptyloxy)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)phenyl)propanoateas a colorless oil. LCMS-ESI (m/z) calculated for C₃₇H₅₅N₃O₆Si: 665.9;found 666.4 [M+H]⁺, t_(R)=3.10 min (Method 8).

(S)-methyl2-amino-3-(4-(4-(4-(heptyloxy)phenyl)-1H-imidazol-2-yl)phenyl)-propanoate

(S)-methyl2-amino-3-(4-(4-(4-(heptyloxy)phenyl)-1H-imidazol-2-yl)phenyl)propanoatewas prepared from (S)-methyl2-((tert-butoxycarbonyl)amino)-3-(4-(4-(4-(heptyloxy)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)phenyl)propanoate using General Procedure 8. LCMS-ESI (m/z) calculated forC₂₆H₃₃N₃O₃: 435.6; found 436.3 [M+H]⁺, t_(R)=1.43 min (Method 8).

(S)-2-(4-(tert-butyl)benzamido)-3-(4-(4-(4-(heptyloxy)phenyl)-1H-imidazol-2-yl)phenyl)propanoicacid hydrochloride (Compound 286)

To a solution of 4-(tert-butyl)benzoic acid (25 mg, 0.14 mmol),(S)-methyl2-amino-3-(4-(4-(4-(heptyloxy)phenyl)-1H-imidazol-2-yl)phenyl)propanoate(55 mg, 0.13 mmol), and TEA (53 μl, 0.38 mmol) in DMF (1 mL) was addedHATU (53 mg, 0.14 mmol). The reaction mixture was stirred at RT for 2 h,diluted in DCM, and washed aq. NaHCO₃. The organic layer was dried,concentrated and purified by chromatography (EA/hexane) to provide 14 mg(17%) of methyl(S)-2-(4-(tert-butyl)benzamido)-3-(4-(4-(4-(heptyloxy)phenyl)-1H-imidazol-2-yl)phenyl)propanoate.LCMS-ESI (m/z) calculated for C₃₇H₄₅N₃O₄: 595.8; found 596.4 [M+H]⁺,t_(R)=2.33 min. (Method 8).

The isolated ester intermediate was deprotected using General Procedure4 to provide 14 mg (17.5%) of(S)-2-(4-(tert-butyl)benzamido)-3-(4-(4-(4-(heptyloxy)phenyl)-1H-imidazol-2-yl)phenyl)propanoicacid hydrochloride Compound 286 as a light tan solid. LCMS-ESI (m/z)calculated for C₃₆H₄₃N₃O₄: 581.8; found 582.4 [M+H]⁺, t_(R)=6.56 min(Method 9).

4-bromo-1-(4-(heptyloxy)phenyl)-1H-imidazole

Into a vial was charged (4-(heptyloxy)phenyl)boronic acid (1.00 g, 4.24mmol), 4-bromo-1H-imidazole (0.31 g, 2.1 mmol), Cu-(TMEDA)₂(OH)₂Cl₂(0.10 g, 0.21 mmol) and DCM (12 ml). After stirring at RT for 42 h, themixture was purified by chromatography (EA/hexane) to provide 80 mg ofimpure product. Further purification by chromatography (CAN/DCM)provided 42 mg (6%) of 4-bromo-1-(4-(heptyloxy)phenyl)-1H-imidazole as acolourless oil. LCMS-ESI (m/z) calculated for C₁₆H₂₁BrN₂O: 336.1; found337.1 [M+H]⁺, t_(R)=2.71 min (Method 8).

(S)-2-(4-(tert-butyl)benzamido)-3-(4-(1-(4-(heptyloxy)phenyl)-1H-imidazol-4-yl)phenyl)propanoicacid (Compound 287)

Prepared using General Procedure 10. Into a vial containing INT-13 (96mg, 0.19 mmol) and 4-bromo-1-(4-(heptyloxy)phenyl)-1H-imidazole (64 mg,0.19 mmol) in 2/2/1 THF/CAN/H₂O (3 mL) was added Na₂CO₃ (40 mg, 0.38mmol). The reaction mixture was degassed and Pd(dppf)Cl₂ (14 mg, 0.02mmol) was added. After heating at 120° C. for 30 min in a microwavereactor, the mixture was diluted with EA, washed with aq. NaHCO₃, driedover MgSO₄ and concentrated. Purification by chromatography (EA/hexanes)provided 14 mg (12%) of the intermediate tert-butyl(S)-2-(4-(tert-butyl)benzamido)-3-(4-(1-(4-(heptyloxy)phenyl)-1H-imidazol-4-yl)phenyl)propanoateas a white solid.

The intermediate was deprotected according to General Procedure 8 toprovide 9 mg (8%) of(S)-2-(4-(tert-butyl)benzamido)-3-(4-(1-(4-(heptyloxy)phenyl)-1H-imidazol-4-yl)phenyl)propanoicacid, Compound 287 as a white solid. LCMS-ESI (m/z) calculated forC₃₆H₄₃N₃O₄: 581.3; found 582.2 [M+H]⁺, t_(R)=8.33 min (Method 9).

(S)-2-(4-(tert-butyl)benzamido)-3-(4-(1-(4′-methyl-[1,1′-biphenyl]-4-yl)-1H-pyrazol-4-yl)phenyl)propanoicacid (Compound 288)

Prepared using General Procedure 10. Into a vial containing INT-13 (100mg, 0.20 mmol) and4-bromo-1-(4′-methyl-[1,1′-biphenyl]-4-yl)-1H-pyrazole (63 mg, 0.201mmol) in 2/1 ACN/H₂O (3 mL) was added sat aq. NaHCO₃ (670 μL, 0.60mmol). The reaction mixture was degassed and Pd(dppf)Cl₂ (15 mg, 0.02mmol) was added. After heating at 120° C. for 60 min in a microwavereactor, the mixture was diluted with DCM, washed with aq. NaHCO₃,passed through a phase separation cartridge, and concentrated.Purification by chromatography (EA/hexane) provided 58 mg (47%) of theintermediate tert-butyl(S)-2-(4-(tert-butyl)benzamido)-3-(4-(1-(4′-methyl-[1,1′-biphenyl]-4-yl)-1H-pyrazol-4-yl)phenyl)propanoateas a white solid. LCMS-ESI (m/z) calculated for C₄₀H₄₃N₃O₃: 613.8; found614.0 [M+H]⁺, t_(R)=3.02 min (Method 8). The intermediate was stirred in4M HCl/dioxane for 132 h and filtered. The resulting solid was washedwith hexane to provide 13 mg of solid product. The filtrate was loadedonto a strong anion exchange (SAX) column, washed with MeOH, and elutedwith 5% AcOH in MeOH. The elution liquors were combined with thetrituration solid and concentrated in vacuo to afford 18 mg (32%) of(S)-2-(4-(tert-butyl)benzamido)-3-(4-(1-(4′-methyl-[1,1′-biphenyl]-4-yl)-1H-pyrazol-4-yl)phenyl)propanoicacid 288 as a white solid. LCMS-ESI (m/z) calculated for C₃₆H₃₅N₃O₃:557.3; found 558.0 [M+H]⁺, t_(R)=9.37 min (Method 9).

Methyl2-(4-bromophenyl)-2-(5-(tert-butyl)thiophene-2-carboxamido)acetate

Prepared using General Procedure 7. To a solution of methyl2-amino-2-(4-bromophenyl)acetate, HCl (730 mg, 2.6 mmol),5-(tert-butyl)thiophene-2-carboxylic acid (480 mg, 2.6 mmol) and TEA(1090 μl, 7.8 mmol) in DMF (10 mL) was added HATU (1090 mg, 2.9 mmol).After stirring overnight, the reaction mixture was diluted with EA (100mL) and washed with 1M HCl (100 mL) and brine. The organic layer wasdried over Mg₂SO₄, concentrated, and purified by chromatography(EA/hexane) to provide 900 mg (76%) of methyl2-(4-bromophenyl)-2-(5-(tert-butyl)thiophene-2-carboxamido)acetate as awhite powder. LCMS-ESI (m/z) calculated for C₁₈H₂₀BrNO₃S: 410.3; found412.0 [M+2]⁺, t_(R)=2.71 min (Method 8).

Methyl2-(5-(tert-butyl)thiophene-2-carboxamido)-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate

Prepared using General Procedure 10. A solution of2-(4-bromophenyl)-2-(5-(tert-butyl)thiophene-2-carboxamido)acetate (900mg, 2.2 mmol), KOAc (650 mg, 6.6 mmol) and4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (670 mg, 2.6mmol) in DMSO (10 mL) at 40° C. was de-gassed. PdCl₂dppf (80 mg, 0.11mmol) was added and the mixture was heated at 100° C. for 3 h. Thereaction mixture was purified by chromatography (EA/hexane with 1% TEA)to provide 491 mg (41%) of methyl2-(5-(tert-butyl)thiophene-2-carboxamido)-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate. LCMS-ESI (m/z) calculated for C₂₄H₃₂BNO₅S: 457.4; found458.0 [M+H]⁺, t_(R)=2.89 min (Method 8).

2-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-carboxamido)aceticacid

Prepared using General Procedure 10. A mixture of methyl2-(5-(tert-butyl)thiophene-2-carboxamido)-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl) acetate (320 mg, 0.71 mmol) and 5-bromo-2-iodopyrimidine (220mg, 0.78 mmol) in THF (2 mL) and MeCN (2 mL) was treated with saturatedaq. NaHCO₃ (1600 μl, 1.40 mmol) and de-gassed (N₂ bubbling). PdCl₂dppf(26 mg, 0.04 mmol) was added and the mixture was heated at 120° C. for30 min in a microwave reactor. The mixture was poured onto H₂O (30 mL),acidified with AcOH and extracted with EA (3×15 mL). The combinedorganics were dried over MgSO₄, evaporated, and purified bychromatography (EA/hexane with 1% AcOH) to provide 160 mg (46%) of2-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-carboxamido)aceticacid as a white solid. LCMS-ESI (m/z) calculated for C₂₁H₂₀BrN₃O₃S:473.0; found 474.0 [M+H]⁺, t_(R)=2.68 min (Method 8).

(S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(heptyloxy)phenyl)-pyrimidin-2-yl)phenyl)propanoicacid (Compound 289)

Prepared using General Procedure 10. A solution of2-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-carboxamido)aceticacid (160 mg, 0.34 mmol), (4-(heptyloxy)phenyl)boronic acid (94 mg, 0.40mmol) and sat aq. NaHCO₃ (930 μl, 0.84 mmol) in ACN (1.5 mL) and THF(1.5 mL) was degassed (N₂ bubbling). PdCl₂(dppf) (262 mg, 0.34 mmol) wasadded and the reaction mixture was heated at 110° C. in a microwavereactor for 50 min. The reaction was partitioned between EA and H₂O. Theorganic layer was dried over MgSO₄, filtered, concentrated and purifiedby chromatography (EA/hexane with 1% AcOH) to afford 113 mg (55%) of2-(5-(tert-butyl)thiophene-2-carboxamido)-2-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)aceticacid Compound 289 as a white solid. LCMS-ESI (m/z) calculated forC₃₄H₃₉N₃O₄S: 585.3; found 586.0 [M+H]⁺, t_(R)=3.37 min (Method 9).

(S)—N-(1-amino-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)-1-oxopropan-2-yl)-4-(tert-butyl)benzamide

A solution of Compound 85 (245 mg, 0.413 mmol) in DMF (5 mL) was treatedwith NH₄Cl (180 mg, 3.3 mmol), DIEA (760 μl, 4.1 mmol) and HATU (170 mg,0.4 mmol). After stirring overnight, the reaction mixture was dilutedwith EA (50 mL), washed with aq. 0.5 M HCl (100 mL) and brine (20 mL),then dried over MgSO₄ and concentrated. The residue was re-slurried fromACN (4 mL) to afford 204 mg (77%) of(S)—N-(1-amino-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)-1-oxopropan-2-yl)-4-(tert-butyl)benzamideas a fine white solid. LCMS-ESI (m/z) calculated for C₃₇H₄₄N₄O₃: 592.3;found 593.0 [M+H]⁺, t_(R)=3.43 min (Method 6).

(S)-methyl 3-(4-(tert-butyl)benzamido)-4-(4-hydroxyphenyl)butanoate

Prepared using General Procedure 7. A solution of (S)-methyl3-amino-4-(4-hydroxyphenyl)butanoate hydrochloride (2.1 g, 8.7 mmol),4-(tert-butyl)benzoic acid (1.6 g, 9.0 mmol) and DIEA (3.5 ml, 18.8mmol) in DMF (20 mL) and DCM (20 mL) was treated with HATU (3.3 g, 8.5mmol). After 1 h, the mixture was poured onto 1M HCl (100 mL) andextracted with EA (3×50 mL). The combined organic extracts were washedsuccessively with 1M HCl (50 mL), water (50 mL) and brine (20 mL), thendried over MgSO₄ and concentrated. The resulting residue was purified bychromatography (EA/hexane) to provide 2.3 g (72%) of (S)-methyl3-(4-(tert-butyl)benzamido)-4-(4-hydroxyphenyl) butanoate as whiteneedles. LCMS-ESI (m/z) calculated for C₂₂H₂₇NO: 369.4, found 370.0[M+H]⁺, t_(R)=2.52 min (Method 6).

(S)-methyl3-(4-(tert-butyl)benzamido)-4-(4-(((trifluoromethyl)sulfonyl)oxy)-phenyl)butanoate

Prepared using General Procedure 9. A stirred solution of (S)-methyl3-(4-(tert-butyl)benzamido)-4-(4-hydroxyphenyl) butanoate (2.30 g, 6.3mmol) in DCM (25 mL) was treated with DIEA (1.4 ml, 7.6 mmol) then1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide(2.5 g, 6.9 mmol). After 18 h, the reaction mixture was diluted with DCM(100 mL), H₂O (50 mL) and NaHCO₃ (75 mL) and stirred for 1 h. Theorganic layer was isolated, washed with NaHCO₃ (100 mL), dried overMgSO₄, concentrated, and purified by chromatography (EA/hexane) toprovide 2.5 g (75%) of (S)-methyl3-(4-(tert-butyl)benzamido)-4-(4-(((trifluoromethyl)sulfonyl)oxy)phenyl)butanoateas a thick oil. LCMS-ESI (m/z) calculated for C₂₃H₂₆F₃NO₆S: 501.5, found502 [M+H]⁺, t_(R)=3.20 min (Method 6).

(S)-methyl3-(4-(tert-butyl)benzamido)-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)butanoate

To a vial under a N₂ atmosphere were added4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (530 mg, 2.1mmol), (S)-methyl3-(4-(tert-butyl)benzamido)-4-(4-(((trifluoromethyl)sulfonyl)oxy)phenyl)butanoate(810 mg, 1.6 mmol), KOAc (280 mg, 4.8 mmol) and DMSO (14 mL). Thesolution was degassed. Pd(dppf)Cl₂ (59 mg, 0.08 mmol) was added and thesolution was heated to 80° C. for 6 h. The reaction mixture was cooledto RT, diluted with EA (100 mL) and washed with sat aq. NaHCO₃ (50 ml)and brine (50 mL). The organic layer was dried over MgSO₄, concentratedand purified by chromatography (EA/hexane) to afford 446 mg (57%) of(S)-methyl3-(4-(tert-butyl)benzamido)-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)as a colorless crystalline solid. LCMS-ESI (m/z) calculated forC₂₈H₃₈BNO₅: 479.4, found 480.3 [M+H]⁺, t_(R)=2.86 min (Method 6).

(S)-methyl4-(4-(5-bromopyrimidin-2-yl)phenyl)-3-(4-(tert-butyl)benzamido)-butanoate

Prepared using General Procedure 10. Into a vial were added (S)-methyl3-(4-(tert-butyl)benzamido)-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)(390 mg, 0.81 mmol), 5-bromo-2-iodopyrimidine (240 mg, 0.85 mmol),Na₂CO₃ (170 mg, 1.6 mmol), THF (1.5 mL), ACN (1.5 mL) and H₂O (0.75 mL).The solution was degassed and PdCl₂(dppf) (60 mg, 0.08 mmol) was added.The reaction mixture was heated in a microwave reactor at 110° C. for 60min. The sample was cooled, diluted with EA (50 mL), and washed with sataq.NaHCO₃ (30 mL). The organic layers were dried over MgSO₄, filtered,concentrated, and purified by chromatography (EA/hexane) to afford 205mg (49%) of (S)-methyl4-(4-(5-bromopyrimidin-2-yl)phenyl)-3-(4-(tert-butyl)benzamido)butanoateas a colourless solid. LCMS-ESI (m/z) calculated for C₂₆H₂₈BrN₃O₃:510.4, found 512.2 [M+H]⁺, t_(R)=2.77 min (Method 6).

(S)-3-(4-(tert-butyl)benzamido)-4-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)butanoicacid (Compound 291)

Prepared using General Procedures 10 and 4. Into a vial were added(S)-methyl4-(4-(5-bromopyrimidin-2-yl)phenyl)-3-(4-(tert-butyl)benzamido)butanoate(180 mg, 0.35 mmol), (4-(heptyloxy)phenyl)boronic acid (98 mg, 0.41mmol), Na₂CO₃ (73 mg, 0.69 mmol), ACN (1.2 mL), THF (1.2 mL) and H₂O(0.7 mL). The solution was degassed, Pd(dppf)Cl₂ (25 mg, 0.03 mmol) wasadded, and the reaction mixture was heated in a microwave reactor at110° C. for 80 min. The reaction mixture was diluted with EA (50 mL) andwashed with sat aq. NaHCO₃ (30 mL). The organics layer was dried overMgSO₄, concentrated, and purified by chromatography (EA/hexane) toafford 44 mg of methyl ester intermediate. The solid was dissolved inTHF (1 mL) and 1M LiOH (1 mL). The solution was stirred at ambienttemperature for 1 h, concentrated, and 1M HCl (1.5 mL) was added. Thesolid was collected by filtration, washing with water (2×5 mL) andhexane (2×5 mL) to provide 19 mg (9%) of(S)-3-(4-(tert-butyl)benzamido)-4-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)butanoicacid Compound 291 as a colorless solid. LCMS-ESI (m/z) calculated forC₃₈H₄₅N₃O₄: 607.8, found 608.4 [M+H]⁺, t_(R)=10.99 min (Method 10).

5-bromo-2-chloro-4-methoxypyrimidine

To a stirred solution of 5-bromo-2,4-dichloropyrimidine (500 mg, 2.19mmol) in MeOH (5 mL) was added a 30% solution of sodium methoxide (0.40mL, 2.26 mmol). The reaction mixture was stirred at RT for 2 h thenconcentrated. The residue was dissolved in water (5 mL) and extractedwith EA (3×5 mL). The combined organic layer was washed with brine,dried over MgSO₄ and concentrated to afford 432 mg (88%) of5-bromo-2-chloro-4-methoxypyrimidine as white solid. LCMS-ESI (m/z)calculated for C₅H₄BrClN₂O: 223.4; found 224.2 [M+H]⁺, t_(R)=7.66 min.(Method 2).

5-bromo-2-iodo-4-methoxypyrimidine

Prepared using General Procedure 16: To a stirred solution of5-bromo-2-chloro-4-methoxypyrimidine (100 mg, 0.447 mmol) in 57% aq. HI(1.0 mL) was added sodium iodide (125 mg, 0.838 mmol). The reactionmixture was stirred at 40° C. for 16 h, cooled, then quenched withNaHCO₃ (5 mL) and extracted with EA (3×5 mL). The combined organics werewashed with brine, dried over MgSO₄ and concentrated to afford 22.0 mg(16%) of 5-bromo-2-iodo-4-methoxypyrimidine as an off-white solid.LCMS-ESI (m/z) calculated for C₅H₄BrIN₂O: 314.9; found 315.9 [M+H]⁺,t_(R)=8.22 min. (Method 2). ¹H NMR (400 MHz, DMSO) δ 8.25 (s, 1H), 4.07(s, 3H).

Tert-butyl(S)-3-(4-(5-bromo-4-methoxypyrimidin-2-yl)phenyl)-2-(4-(tert-butyl)benzamido)propanoate

Prepared using General Procedure 10: A mixture of tert-butyl(S)-2-(4-(tert-butyl)benzamido)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoateINT-13 (30.0 mg, 0.06 mmol), 5-bromo-2-iodo-4-methoxypyrimidine (22.3mg, 0.07 mmol), and sodium carbonate (12.5 mg, 0.12 mmol) inacetonitrile (0.80 mL), THF (0.80 mL) and H₂O (0.40 mL) was degassed for10 min. Pd(dppf)Cl₂:CH₂Cl₂ (5 mg, 0.005 mmol) was added and the reactionmixture heated at 110° C. in a microwave for 30 min. Once cooled, thereaction was diluted with NaHCO₃ (5 mL), extracted with EA (3×5 mL) andthe combined organics dried over MgSO₄ and concentrated. The residue waspurified by column chromatography (EA/hexanes) to afford 20.0 mg (60%)of tert-butyl(S)-3-(4-(5-bromo-4-methoxypyrimidin-2-yl)phenyl)-2-(4-(tert-butyl)benzamido)propanoateas a white solid. LCMS-ESI (m/z) calculated for C₂₉H₃₄BrN₃O₄: 568.5;found 514.2 [M-tBu+H]⁺, t_(R)=11.0 min. (Method 2).

Tert-butyl(S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)-4-methoxypyrimidin-2-yl)phenyl)propanoate

Prepared using General Procedure 10: A mixture of tert-butyl(S)-3-(4-(5-bromo-4-methoxypyrimidin-2-yl)phenyl)-2-(4-(tert-butyl)benzamido)propanoate(18.0 mg, 0.031 mmol), (4-(heptyloxy)phenyl)boronic acid (10.0 mg, 0.042mmol) and sodium carbonate (8.97 mg, 0.084 mmol) in acetonitrile (0.80mL), THF (0.80 mL) and H₂O (0.40 mL) was degassed for 10 min.Pd(dppf)Cl₂:CH₂Cl₂ (3.09 mg, 0.003 mmol) was added and the reactionmixture heated at 110° C. in a microwave for 30 min. Once cooled, thereaction was diluted with NaHCO₃ (5 mL) and extracted with EA (3×5 mL).The combined organics were dried over MgSO₄ and concentrated. Theresidue was purified by column chromatography (EA:hexanes) to afford20.0 mg (60%) of tert-butyl(S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)-4-methoxypyrimidin-2-yl)phenyl)propanoateas pale yellow solid. LCMS-ESI (m/z) calculated for C₄₂H₅₃N₃O₅: 679.8;no ion observed, t_(R)=13.83 min. (Method 2).

(S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)-4-methoxypyrimidin-2-yl)phenyl)propanoicacid (Compound 292)

Prepared using General Procedure 8: A solution of tert-butyl(S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl-4-methoxypyrimidin-2-yl)phenyl)propanoate (20.0 mg, 0.029 mmol) in DCM (1 mL) was treated with TFA(0.350 mL). The reaction mixture was stirred at RT for 12 h. The solventwas concentrated and the product was purified preparative HPLC to yield15.0 mg (82%) of(S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)-4-methoxypyrimidin-2-yl)phenyl)propanoicacid, Compound 292 as pale yellow solid. LCMS-ESI (m/z) calculated forC₃₈H₄₅N₃O₅: 623.8; no ion observed, t_(R)=12.17 min. (Method 2).

Compound 293 was prepared using tert-butyl(S)-2-(4-(tert-butyl)benzamido)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoateINT-13 and 5-bromo-2-chloro-N,N-dimethylpyrimidin-4-amine using GeneralProcedures 10, 10 and 8 sequentially.

Compound 294 was prepared using tert-butyl(S)-2-(4-(tert-butyl)benzamido)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoateINT-13 and 5-bromo-2-iodo-4-methylpyridine using General Procedures 10,10 and 8 sequentially

5-bromo-2-iodo-4-(trifluoromethyl)pyridine

Prepared using General Procedure 17: To a stirred a solution of5-bromo-2-chloro-4-(trifluoromethyl)pyridine (150 mg, 0.576 mmol) inacetonitrile (2 mL) was added sodium iodide (518 mg, 3.45 mmol). Thereaction mixture was heated to 40° C. and acetyl chloride (26.0 mg,0.345 mmol) was added. The reaction mixture was stirred at 40° C. for 90min. Once cooled, the reaction was quenched with NaHCO₃ (5 mL) andextracted with EA (3×5 mL). The combined organics were washed with brine(10 mL), dried over MgSO₄ and concentrated to give 80.0 mg (40%) of5-bromo-2-iodo-4-(trifluoromethyl)pyridine as a white crystalline solidwhich was used in the subsequent step without purification. LCMS-ESI(m/z) calculated for C₆H₂BrF₃IN, 351.9; found 352.5 [M+H]⁺, t_(R)=3.91min. (Method 1).

Compound 295 was prepared by employing tert-butyl(S)-2-(4-(tert-butyl)benzamido)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoateINT-13 and 5-bromo-2-iodo-4-(trifluoromethyl)pyridine using GeneralProcedures 10, 10 and 8 sequentially.

(S)-(2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoyl)glycine(Compound 297)

Prepared using General Procedures 7 and 8: To a solution of(S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoicacid Compound 85 (185 mg, 0.312 mmol), tert-butyl 2-aminoacetatehydrochloride (52.2 mg, 0.312 mmol), and DIEA (163 μl, 0.935 mmol) inDMF (3 mL) was added HATU (124 mg, 0.327 mmol). The mixture was stirredfor 1 h at RT. The crude material was diluted in EA (50 mL), washed withsaturated aqueous sodium bicarbonate (20 mL) and brine (20 mL). Theorganic layer was dried over MgSO₄, filtered, and the solvent removedunder reduced pressure. The crude product was purified by chromatography(EA/hexanes) to afford the intermediate tert-butyl ester (110 mg).

The tert-butyl ester was dissolved in DCM (1 mL) and TFA (2 mL) wasadded. The solution was stirred at RT for 3 h and the solvent wasremoved under reduced pressure. The crude mixture was dissolved in DMSO(0.8 mL) and precipitated by the addition of water (3 mL). Theprecipitate was filtered, washed with water (3 mL) and hexane (2×2 mL)to yield 58 mg (28%) of(S)-(2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoyl)glycine, Compound 297 as a colorless solid. LCMS-ESI (m/z)calculated for C₃₉H₄₆N₄O₅: 650.4; found 651.4 [M+H]⁺, t_(R)=10.43 min(Method 10). The chiral purity was calculated at 92% e.e. (ChiralMethod). ¹H NMR (400 MHz, DMSO-d6) δ 12.62 (s, 1H), 9.15 (s, 2H), 8.60(d, J=8.6 Hz, 1H), 8.49-8.40 (m, 1H), 8.35-8.25 (m, 2H), 7.84-7.70 (m,4H), 7.58-7.49 (m, 2H), 7.48-7.41 (m, 2H), 7.16-7.02 (m, 2H), 4.90-4.75(m, 1H), 4.03 (t, J=6.5 Hz, 2H), 3.93-3.75 (m, 2H), 3.25 (dd, J=13.8,3.8 Hz, 1H), 3.09 (dd, J=13.7, 11.2 Hz, 1H), 1.79-1.68 (m, 2H),1.51-1.21 (m, 17H), 0.94-0.80 (m, 3H).

(S)-3-(2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanamido)propanoicacid (Compound 298)

Prepared using General Procedures 7 and 8: HATU (116 mg, 0.31 mmol) wasadded to a stirring solution of(S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoicacid Compound 85 (173 mg, 0.29 mmol), tert-butyl 3-aminopropanoatehydrochloride (53 mg, 0.29 mmol) and DIEA (153 μl, 0.87 mmol) in DMF (3mL). The crude material was diluted in EA (50 mL), washed with saturatedaqueous sodium bicarbonate (20 mL) and brine (20 mL). The organic layerwas dried over MgSO₄, filtered, and the solvent removed under reducedpressure. The crude product was purified by chromatography (EA/hexanes)to afford the intermediate tert-butyl ester (122 mg).

The tert-butyl ester was dissolved in DCM (1 mL) and TFA (2 mL) wasadded. The reaction mixture was stirred at RT for 3 h and the solventwas removed under reduced pressure. The crude mixture was dissolved inDMSO (0.8 mL) and precipitated by the addition of water (3 mL). Theprecipitate was filtered, washed with water (3 mL) and hexane (2×2 mL)to yield 48 mg (25%) of(S)-3-(2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanamido)propanoicacid, Compound 298 as a colorless solid. LCMS-ESI (m/z) calculated forC₄₀H₄₈N₄O₅: 664.4; found 665.4 [M+H]⁺, t_(R)=10.36 min (Method 10). ¹HNMR (400 MHz, DMSO-d6) δ 12.26 (s, 1H), 9.15 (s, 2H), 8.51 (d, J=8.5 Hz,1H), 8.40-8.25 (m, 2H), 8.25-8.14 (m, 1H), 7.96-7.65 (m, 4H), 7.65-7.36(m, 4H), 7.28-6.99 (m, 2H), 4.84-4.64 (m, 1H), 4.03 (t, J=6.5 Hz, 2H),3.32-3.24 (m, 2H), 3.17 (dd, J=13.7, 4.4 Hz, 1H), 3.06 (dd, J=13.7, 10.4Hz, 1H), 2.41 (t, J=6.9 Hz, 2H), 1.81-1.68 (m, 2H), 1.50-1.20 (m, 17H),0.88 (t, J=6.7 Hz, 3H).

(S)-4-(tert-butyl)-N-(3-(4 (5 (4(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)-1-(methylsulfonamido)-1-oxopropan-2-yl)benzamide(Compound 299)

To a solution of(S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoicacid Compound 85 (78.0 mg, 0.13 mmol), methanesulfonamide (20.0 mg, 0.21mmol), and DMAP (16.1 mg, 0.13 mmol) in DMF (1.5 mL) was added EDC (40.3mg, 0.21 mmol) and the solution stirred overnight at RT. The reactionmixture was diluted in EA (50 mL), washed with aqueous saturated sodiumbicarbonate (2×20 mL) and brine (20 mL). The organic layer was driedover MgSO₄, filtered, and the solvent removed under reduced pressure.The crude product was purified by chromatography (hexane/EA) to afford36 mg (40%) of(S)-4-(tert-butyl)-N-(3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)-1-(methylsulfonamido)-1-oxopropan-2-yl)benzamide, Compound 299 as a colorless solid. LCMS-ESI (m/z) calculated forC₃₈H₄₆N₄O₅S: 670.3; found 671.3 [M+H]⁺, t_(R)=11.01 min (Method 10).

Compounds 300-304 were prepared from(S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoicacid Compound 85 using General Procedures 3 or 7 followed by 4 or 8.

Compounds 305-317 were prepared from(S)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)-2-(4-isopropylbenzamido)propanoicacid Compound 94 using General Procedures 3 or 7 followed by 4 or 8.

Compound 318 was prepared from(S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(hexyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoicacid Compound 225 using General Procedures 7 followed by 8.

(S)-(2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoyl)glycine(Compound 319)

Prepared using General Procedures 7 and 4: TEA (93 μl, 0.67 mmol) wasadded to a solution of(S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoicacid Compound 192 (100 mg, 0.167 mmol), methyl 2-aminoacetatehydrochloride (23.03 mg, 0.18 mmol) and HATU (76 mg, 0.20 mmol) in DMF(2 mL). The solution was stirred at RT for 18 h. The reaction mixturewas diluted with EA (25 mL) and washed with saturated aqueous NaHCO₃(2×25 mL) and 1 M HCl (2×25 mL). The organic phase was dried over MgSO₄,filtered, and concentrated. The solid was purified by chromatography(EA/hexanes) to afford the methyl ester intermediate as a colorlesssolid.

The solid was dissolved in THF (3 mL) and 1 M LiOH (333 μl, 0.33 mmol)was added. The resultant yellow solution was stirred at RT for 1 h. Thereaction mixture was acidified to pH 1 using 1M HCl and the THF removedin vacuo. The residue was suspended in water and the mixture filteredunder vacuum. The solid was azeotroped with MeOH and dried in a vacuumoven to afford 48 mg (44%) of(S)-(2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoyl)glycine,Compound 319 as a yellow solid. LCMS-ESI (m/z) calculated forC₃₇H₄₄N₄O₅S: 656.3; found 657.0 [M+H]⁺, t_(R)=10.34 min (Method 10). Thechiral purity was calculated at 95% e.e. (Chiral Method). ¹H NMR (400MHz, DMSO-d6) δ 12.61 (s, 1H), 9.16 (s, 2H), 8.62 (d, J=8.7 Hz, 1H),8.51-8.41 (m, 1H), 8.36-8.26 (m, 2H), 7.84-7.75 (m, 2H), 7.68 (d, J=3.8Hz, 1H), 7.55-7.43 (m, 2H), 7.14-7.05 (m, 2H), 6.92 (d, J=3.8 Hz, 1H),4.84-4.72 (m, 1H), 4.03 (t, J=6.5 Hz, 2H), 3.89-3.73 (m, 2H), 3.22 (dd,J=13.9, 3.7 Hz, 1H), 3.10-2.96 (m, 1H), 1.78-1.66 (m, 2H), 1.31 (s,17H), 0.94-0.81 (m, 3H).

((S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoyl)-L-glutamine(Compound 320)

Prepared using General Procedures 7 and 8: To a stirred solution of(S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoic acid Compound 192 (250 mg, 0.42 mmol), (S)-tert-butyl2,5-diamino-5-oxopentanoate hydrochloride (109 mg, 0.46 mmol) and TEA(145 μl, 1.04 mmol) in DMF (4 mL) was added HATU (190 mg, 0.50 mmol) andthe reaction mixture was stirred at RT for 2 h. The reaction mixture wasdiluted with EA (50 mL), washed with 1M HCl (50 mL) and brine (100 mL),dried over magnesium sulfate, and concentrated.

The crude product was dissolved in DCM (5 mL) and TFA (3 mL) was added.After 3 h, toluene (10 mL) was added and the solvent removed. Thecompound was purified by preparative HPLC to afford 78 mg (25%) of((S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoyl)-L-glutamine,Compound 320 as a white powder. LCMS-ESI (m/z) calculated forC₄₀H₄₉N₅O₆S: 727.3; found 728.0 [M+H]⁺, t_(R)=10.71 min (Method 10). Thechiral purity was 90% d.e. (Chiral Method). ¹H NMR (400 MHz, DMSO-d6) δ9.15 (s, 2H), 8.56 (d, J=8.6 Hz, 1H), 8.42-8.34 (m, 1H), 8.34-8.27 (m,2H), 7.84-7.75 (m, 2H), 7.66 (d, J=3.9 Hz, 1H), 7.54-7.48 (m, 2H), 7.32(s, 1H), 7.12-7.04 (m, 2H), 6.90 (d, J=3.8 Hz, 1H), 6.77 (s, 1H),4.81-4.65 (m, 1H), 4.19-4.11 (m, 1H), 4.03 (t, J=6.5 Hz, 2H), 3.20 (dd,J=14.1, 3.5 Hz, 1H), 3.07-2.96 (m, 1H), 2.24-2.09 (m, 2H), 2.06-1.93 (m,1H), 1.90-1.79 (m, 1H), 1.78-1.68 (m, 2H), 1.47-1.20 (m, 17H), 0.93-0.82(m, 3H).

Compounds 321-350 were prepared from Compound 192 using GeneralProcedures 3 or 7 followed by 4 or 8.

Compounds 351-368 were prepared from Compound 165 using GeneralProcedures 7 followed by 4 or 8.

Compound 369 was prepared from Compound 139 using General Procedures 7followed by 8.

Compound 370 was prepared from Compound 167 using General Procedures 7followed by 8.

Compound 371 was prepared from Compound 142 using General Procedures 7followed by 8.

Compound 372 was prepared from Compound 143 using General Procedures 7followed by 8.

Compound 373 was prepared from Compound 182 using General Procedures 7followed by 8.

Compounds 374-379 were prepared from Compound 193 using GeneralProcedures 3 or 7 followed by 4 or 8.

Compound 380 was prepared from Compound 191 using General Procedures 7followed by 8.

(S)-4-(tert-butyl)-N-(3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)-1-(2-(methylsulfonamido)-2-oxoethyl)amino)-1-oxopropan-2-yl)benzamide(Compound 381)

TEA (32.1 μl, 0.23 mmol) was added to a suspension of(S)-(2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoyl)glycineCompound 297 (75.0 mg, 0.11 mmol), methanesulfonamide (12.1 mg, 0.13mmol), HATU (52.6 mg, 0.14 mmol) and DMAP (1.41 mg, 0.01 mmol) in DCM (2mL). The resultant yellow suspension was stirred at RT for 3 h. Thereaction mixture was washed with saturated aqueous NaHCO₃ (2 mL) and themixture passed through a phase separation cartridge. The organic phasewas concentrated in vacuo to afford a yellow solid. The crude productwas purified by chromatography (EA/1% AcOH in hexanes) to afford 9 mg(11%)(S)-4-(tert-butyl)-N-(3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)-1-((2-(methylsulfonamido)-2-oxoethyl)amino)-1-oxopropan-2-yl)benzamide,Compound 381 as a yellow solid. LCMS-ESI (m/z) calculated forC₄₀H₄₉N₅O₆S: 727.3; found 728.0 [M+H]⁺, t_(R)=10.51 min (Method 10).

Selected compounds and their corresponding analytical data are shown inTable 1, where the LCMS data was collected using the method indicated.

TABLE 1 LCMS COM- RETEN- PUR- POUND TION ITY NUM- TIME METH- STRUCTUREBER (min) OD

 1 12.42  2

 2 12.17  2

 3 11.65  2

 4 11.13  2

 5 10.65  2

 6 11.66  2

 7 10.04  2

 8 10.92  2

 9  9.58  2

 10 10.69  2

 11 10.13  2

 13 11.46  2

 14 11.45  2

 15 10.95  2

 16 11.55  2

 17 11.04  2

 18 10.66  2

 19 10.69  2

 20 10.78  2

 21 10.74  2

 22 10.75  2

 23 10.66  2

 24 10.72  2

 25 10.50  2

 26 10.53  2

 27 11.48  2

 28 10.05  2

 29 10.07  2

 30 10.03  2

 31  9.83  2

 32 10.77  2

 33 10.75  2

 34 11.00  2

 35 11.09  2

 36  9.19  2

 37 10.98  2

 38  9.93  2

 39  9.30  2

 40  9.87  2

 41  8.29  2

 42 10.32  2

 43  8.20  2

 44  8.14  2

 45  9.29  2

 46 11.40  2

 47 10.07  2

 48 10.38  2

 49  9.78  2

 50  9.79  2

 51 11.93  2

 52 10.36  2

 53 10.23  2

 54  7.85  2

 55  8.17  2

 56 10.44  2

 57 10.46  2

 58 10.25  2

 59 10.85  2

 60 10.33  2

 61  7.66  2

 62  8.281  2

 63  9.34  2

 64  9.05  2

 65  9.69  2

 66  6.46  2

 67 11.51  2

 68 10.10  2

 69 11.90  2

 70 11.67  2

 71 11.05  9

 72  9.22  9

 73 11.42  9

 74  9.61  9

 75  9.13  9

 76 10.06  9

 77 10.87  9

 78 11.03  9

 79 11.30  9

 80 11.57  9

 81 11.23  9

 82 11.21  9

 83 10.60  9

 84 11.56  9

 85 11.18  9

 86  9.46  9

 87 10.09  9

 88  9.51  9

 89 10.26  9

 90 10.33  9

 91 10.64  9

 92 10.48  9

 93 10.63  9

 94 10.85 10

 95 10.58  9

 96  9.69  9

 97 10.22  9

 98  9.36  9

 99  8.75  9

100 11.08  9

101 10.70  9

102  8.51  9

104  8.44  9

105  9.46  9

106 11.27  9

107 11.13  9

108  9.88  9

109  9.87  9

110  9.90  9

111  9.86  9

112 11.34  9

113  9.19  9

114  8.49  9

115  7.95  9

116 11.14  2

117 10.15  9

118  9.90  9

119  9.67  9

120 10.41  9

121 10.86  9

122  9.30  9

123  9.02  9

124 10.38  9

125 10.51  9

126  8.38  9

127  8.95  9

128  8.42  9

129 11.13 10

130 10.23 10

131  9.70 10

132 10.27 10

133 10.87 10

134  6.44 10

135 10.67 10

136  9.85 10

137 10.48 10

138 10.13 10

139  9.09 10

140 10.76 10

141 10.83 10

142 10.42 10

143  9.47 10

144  9.83 10

145 10.79 10

146 10.77 10

147 10.86 10

148 10.17 10

149 11.95  2

150 11.83  2

151 12.41  2

152 12.06  2

153 12.37  2

154 11.19  2

155 11.73  2

156 11.40 10

157 11.93  2

158 11.13  2

159  7.23  9

160  8.85  9

161  9.24  9

162  8.83  9

163  9.78  9

164 10.44  2

165  9.69 10

166  8.97 10

167  7.54 10

168  8.35 10

169  9.32 10

170  8.23 10

171  8.67 10

172 10.31 10

173  9.27 10

174  9.17 10

175  7.34 10

176  7.97 10

177  8.87 10

178  7.94 10

179  9.31 10

180  8.79 10

181  8.11 10

182  9.75 10

183  9.13  9

184 10.87  2

185 11.32  2

186 11.02  2

187 11.21  2

188 11.56  2

189 11.25  2

190 11.42  2

191 11.59 10

192 11.10 10

193 11.17 10

194  7.39  9

195  9.15  9

196  9.30  2

197  9.41  2

198  9.40  2

199 10.53  2

200 10.11  2

201  9.58  2

202  9.51  2

203 10.05  2

204 10.55  2

205 10.36  2

206  9.36  2

207  9.41  2

208  9.49  2

209  9.85  2

210  9.69  2

211  9.81  2

212 10.13  2

213 10.28  2

214  8.69  2

215  9.37  2

216  8.75  2

217  9.83  2

218 10.31  2

219 11.69  2

220 11.97  2

221  9.89  2

222 10.27  2

223 10.46  2

224 10.82  2

225 11.81  2

226 10.15  2

227 10.31  2

228 10.74  2

229 11.03  2

230 10.87  2

231 10.29  2

232  7.95  2

233  8.64  2

234  8.34  2

235  8.94  2

236  9.02  2

237 10.95  2

238 11.19  2

239 11.53  2

240 10.18  2

241 10.30  2

242 10.79  2

243 11.26  2

244 10.10  2

245 10.58  2

246 11.33  2

247 11.19  2

248 11.03  2

249 13.49  2

250 14.78  2

251 16.51  2

252 19.99  2

253 10.79  2

254  7.29  2

255 10.63  2

256 10.99  2

257 11.05  2

258  9.10  2

259 12.41  2

260 12.85  2

261  9.20 10

262 10.23 10

263  7.31  9

264  9.29  9

265 11.47  9

266  8.88  9

267  9.89  9

268 10.33 10

269 10.54  9

270 10.37  9

271 10.92  9

272 11.07  9

273 10.13  9

274 10.61  9

275 10.77  9

276 10.92  2

277 11.90  2

278 10.90  2

279 11.12  2

280 10.30  2

281 12.30  2

282 10.91  2

283 11.00  2

284 11.58  2

285 11.10  2

286  6.56  9

287  8.33  9

288  9.37  9

289  3.37  9

291 10.99 10

292 12.17  2

293  9.21  2

294 11.59  2

295 12.56  2

296 11.25 10

297 10.43 10

298 10.36 10

299 11.01 10

300 11.24  2

301 10.34 10

302 10.67 10

303 10.16 10

304 10.74 10

305 11.39  2

306 11.20  2

307 11.35  2

308 11.61  2

309 11.47  2

310  9.14  2

311  9.52  2

312 11.75  2

313 12.36  2

314  9.14  2

315 11.45  2

316  9.55  2

317 11.18  2

318 11.26  2

319 10.34 10

320 10.71  2

321 11.20  2

322 11.43  2

323  11.312  2

324 11.38  2

325  9.87  2

326 11.34  2

327 11.54  2

328 11.93  2

329 11.90  2

330 11.32  2

331 10.92  2

332  9.53  2

333 11.53  2

334 10.61 10

335 10.87 10

336 10.26 10

337 10.30  2

338 10.36  2

339  8.59 10

340 10.73 10

341 11.28  2

342 11.16 10

343 11.72 10

344 11.13 10

345 10.83 10

346 11.03 10

347 11.60 10

348 11.38 10

349 10.99 10

350 10.91 10

351  9.93 10

352  8.59 10

353  9.91  2

354 10.23  2

355 10.17  2

356  8.40  2

357 10.72  2

358 10.95  2

359 10.17  2

360 10.17  2

361 10.20  2

362 10.98  2

363 10.20  2

364 10.67  2

365  9.14  2

366  8.65  2

367 10.78  2

368 10.84  2

369  8.62 10

370  7.02 10

371 10.12 10

372  9.42 10

373  9.14 10

374 10.78 10

375 10.82 10

376 10.61 10

377 10.16 10

378 10.36 10

379 10.46 10

380 10.74 10

381 10.51 10

Biological Assays Assay Procedures

GLP-1 PAM Shift cAMP Assay: Dose Response of Peptide Ligand in Presenceof Fixed Concentration of Compound.

A GLP-1R expressing CRE-bla CHO-K1 cell line was purchased fromInvitrogen. Cells were seeded into 384-well white flat bottom plates at5000 cells/well/20 μL growth media (DMEM-High glucose, 10% dialyzed FBS,0.1 mM NEAA, 25 mM Hepes, 100 U/mL penicillin/100 μg/mL streptomycin, 5μg/mL Blasticidin, 600 μg/mL Hygromycin) and incubated for 18 h at 37°C. in 5% CO₂. Growth medium was replaced with 12 μL assay buffer (HanksBalanced Salt solution, 10 mM Hepes, 0.1% BSA, pH 7.4). A 5× peptidedose response curve (12-point) was generated in assay buffer containing1.5 mM IBMX, 12.5% DMSO, and 50 μM compound. Peptide ligand wasGLP-1(9-36). The 5× peptide dose response plus compound mix was added (3μL) and cells were incubated for 30 min at 37° C. Direct detection ofcAMP was carried out using DiscoveRx HitHunter cAMP kit according tomanufacturer's instructions and luminescence was read using a SpectraMaxM5 plate reader. Luminescence was analyzed by non-linear regression todetermine the EC₅₀ and Emax. A GLP-1(7-36) dose response was included todetermine maximum efficacy.

EC₂₀ GLP-1(9-36) PAM cAMP Assay: Dose Response of Compound in thePresence of Fixed Concentration of GLP-1 (9-36).

GLP-1R CRE-bla CHO-K1 cells cultured in growth medium (DMEM-Highglucose, 10% dialyzed FBS, 0.1 mM NEAA, 25 mM Hepes, 100 U/mLpenicillin/100 μg/mL streptomycin, 5 μg/mL Blasticidin, 600 μg/mLHygromycin) were tryspsinized and plated in suspension into 384 wellwhite flat bottom plates at 5000 cells/well in 12 μL assay buffer (HanksBalanced Salt solution, 10 mM Hepes, 0.1% BSA, pH 7.4). A 5× compounddose response curve (12-point) was generated in assay buffer containing1.5 mM IBMX, 12.5% DMSO. GLP-1(9-36) was diluted to 4.2 μM in assaybuffer containing 1.5 mM IBMX and 12.5% DMSO. The 5× compound doseresponse was added (3 μL), followed by 0.5 μL of GLP-1(9-36) and cellswere incubated for 30 min at 37° C. Direct detection of cAMP was carriedout using DiscoveRx HitHunter cAMP kit according to manufacturer'sinstructions and luminescence was read using a SpectraMax M5 platereader. Luminescence was converted to total cAMP using a cAMP standardcurve and data was analyzed by non-linear regression to determine theEC₅₀ and Emax.

Peptide Sequences

GLP-1(7-36): HAEGTFTSDVSSYLEGQAAKEFIAWLVKGR-NH₂. GLP-1(9-36):EGTFTSDVSSYLEGQAAKEFIAWLVKGR-NH₂. GLP-1(7-36) was purchased fromGenScript. GLP-1(9-36) was purchased from Biopeptide Co., Inc.

Reported GLP-1 Activity

Activity data for selected GLP-1 modulators are displayed in Table 2.The EC₂₀ GLP-1(9-36) PAM Activity range is denoted as follows: + denotesactivity<0.8 μM, ++ denotes activity between 0.8 and 2.5 μM, +++ denotesactivity between 2.5 and 5 and ++++ denotes activity 5 to 10 μM.

TABLE 2 COMPOUND EC₂₀ GLP-1(9-36) NUMBER PAM EC₅₀ 1 ++ 2 +++ 3 ++++ 4++++ 5 +++ 6 ++++ 7 ++++ 8 ++ 9 ++++ 10 +++ 11 ++ 13 ++ 14 +++ 15 +++ 16++++ 17 +++ 18 ++ 19 ++ 20 ++ 21 +++ 22 +++ 23 +++ 24 ++ 25 ++ 26 +++ 27++ 28 +++ 29 ++ 30 ++ 31 ++ 32 ++++ 33 +++ 34 +++ 35 +++ 36 +++ 37 +++38 ++ 39 ++ 40 +++ 41 +++ 42 +++ 43 +++ 44 +++ 45 ++ 46 ++ 47 +++ 48++++ 49 ++++ 50 +++ 51 +++ 52 ++ 53 +++ 54 +++ 55 +++ 56 +++ 57 +++ 58+++ 59 +++ 60 +++ 61 +++ 62 +++ 63 ++ 64 ++ 65 +++ 66 +++ 67 ++ 68 +++69 ++++ 70 ++++ 71 +++ 72 ++++ 73 ++ 74 +++ 75 +++ 76 ++ 77 ++ 78 ++ 79++ 80 ++ 81 ++++ 82 ++ 83 ++ 84 ++ 85 ++ 86 ++ 87 ++ 88 ++++ 89 ++ 90+++ 91 ++ 92 ++ 93 ++++ 94 ++ 95 ++ 96 +++ 97 ++ 98 ++ 99 ++ 100 ++ 101++ 102 ++ 104 ++ 105 ++++ 106 ++ 107 ++ 108 ++ 109 ++ 110 ++ 111 ++ 112++ 113 ++ 114 ++ 115 ++ 116 ++ 117 + 118 + 119 + 120 ++ 121 ++ 122 ++123 ++ 124 ++ 125 ++ 126 ++ 127 ++ 128 ++ 129 ++ 130 + 131 ++ 132 ++ 133++ 134 ++ 135 ++ 136 ++++ 137 ++ 138 ++ 139 ++ 140 +++ 141 ++ 142 +143 + 144 ++ 145 ++ 146 +++ 147 +++ 148 ++ 149 ++ 150 ++ 151 ++ 152 ++153 ++ 154 + 155 ++ 156 ++ 157 ++ 158 + 159 ++ 160 ++ 161 ++ 162 ++ 163++ 164 ++ 165 ++ 166 ++ 167 ++ 168 ++ 169 ++++ 170 ++ 171 ++ 172 ++ 173++ 174 + 175 + 176 ++++ 177 ++ 178 ++ 179 ++++ 180 + 181 ++ 182 ++ 183++ 184 ++ 185 ++ 186 ++ 187 +++ 188 +++ 189 ++ 190 +++ 191 ++ 192 + 193++ 194 ++ 195 ++ 196 +++ 197 +++ 198 ++++ 199 ++ 200 +++ 201 +++ 202++++ 203 ++++ 204 +++ 205 ++ 206 +++ 207 +++ 208 +++ 209 ++ 210 +++ 211++++ 212 ++++ 213 +++ 214 +++ 215 +++ 216 +++ 217 ++++ 218 +++ 219 ++220 +++ 221 +++ 222 ++ 223 ++ 224 ++ 225 + 226 ++ 227 +++ 228 ++ 229 ++230 ++ 231 ++++ 232 ++ 233 +++ 234 ++++ 235 +++ 236 ++++ 237 ++ 238 ++239 ++ 240 +++ 241 ++ 242 ++ 243 ++ 244 +++ 245 ++ 246 ++ 247 ++ 248 +++249 ++++ 250 ++ 251 ++++ 252 ++++ 253 +++ 254 ++ 255 ++++ 256 ++++ 257++ 258 ++++ 259 ++ 260 + 261 +++ 262 +++ 263 ++ 264 ++ 265 ++++ 266 ++++267 ++ 268 ++ 269 ++ 270 +++ 271 ++ 272 ++ 273 ++ 274 ++ 275 ++ 276 ++277 + 278 +++ 279 ++++ 280 +++ 281 + 282 ++ 283 ++++ 284 ++ 285 ++ 286+++ 287 ++++ 288 +++ 289 +++ 291 ++ 292 ++ 293 +++ 294 ++ 295 ++ 296 ++297 + 298 + 299 + 300 + 301 ++ 302 +++ 303 ++ 304 ++ 305 ++ 306 + 307 ++308 ++ 309 + 310 + 311 ++ 312 ++ 313 ++ 314 ++ 315 ++ 316 + 317 + 318 +319 + 320 + 321 + 322 ++ 323 + 324 ++ 325 ++++ 326 + 327 + 328 ++ 329 ++330 ++ 331 ++ 332 ++ 333 + 334 ++ 335 ++ 336 + 337 ++ 338 ++ 339 ++ 340++ 341 + 342 ++ 343 ++ 344 + 345 + 346 ++ 347 + 348 ++ 349 + 350 + 351 +352 + 353 ++ 354 + 355 ++ 356 ++ 357 ++ 358 ++ 359 ++ 360 ++ 361 ++ 362+++ 363 ++ 364 ++ 365 +++ 366 +++ 367 ++ 368 + 369 ++ 370 ++ 371 + 372 +373 ++ 374 ++ 375 + 376 ++ 377 + 378 + 379 + 380 ++ 381 ++

In Vivo Assays In Vivo Procedures

The oral glucose tolerance test in C57Bl/6 mice.

The use of these compounds to lower glucose can be evaluated in miceusing an oral glucose tolerance test (oGTT). The protocol is describedby Duez et. al (Endocrinology, January 2009, 150(1):56-62). C57BL/6 malemice are chronically cannulated. After a 5 day recovery, mice are fastedfor 4 h. A baseline blood sample is collected before the ivadministration of a bolus of either saline or exendin-4, oradministration of the compound. Immediately after, mice receive a bolusof glucose (1.5 g/kg) by oral gavage (time 0). Blood samples arecollected at frequent time intervals from the tail tip for glucosemeasurement (BD glucometer; Becton-Dickinson, Lincoln Park, N.J.). Forplasma insulin determinations, a blood sample is removed from the tailvein at 5 min after glucose administration.

The Oral Glucose Tolerance Test in Fa/Fa Rats.

The use of these compounds to lower glucose can be evaluated in ratsusing an oral glucose tolerance test (oGTT). The protocol is describedby Pederson et. al. (Diabetes, Vol. 47, August 1998, 1253-1258). Afteran overnight fast, lean or obese animals are administered oral glucoseby syringe and feeding tube (1 g/kg) as a 40% solution (wt/vol).Compound is dissolved and administered along with the glucose. Incontrol experiments, vehicle is administered along with oral glucose.Blood samples are collected from the tail veins of consciousunrestrained rats into heparinized capillary tubes at 0 and 5, 10, 20,30, and 60 min after glucose administration. Blood samples arecentrifuged at 4° C., and plasma is stored at −20° C. until analysis forglucose and insulin measurement. Glucose levels are measured using theglucose oxidase procedure (Beckman glucose analyzer; Fullerton, Calif.).

The various embodiments described above can be combined to providefurther embodiments. All of the U.S. patents, U.S. patent applicationpublications, U.S. patent applications, foreign patents, foreign patentapplications and non-patent publications referred to in thisspecification and/or listed in the Application Data Sheet, areincorporated herein by reference, in their entirety. Aspects of theembodiments can be modified, if necessary to employ concepts of thevarious patents, applications and publications to provide yet furtherembodiments. These and other changes can be made to the embodiments inlight of the above-detailed description. In general, in the followingclaims, the terms used should not be construed to limit the claims tothe specific embodiments disclosed in the specification and the claims,but should be construed to include all possible embodiments along withthe full scope of equivalents to which such claims are entitled.Accordingly, the claims are not limited by the disclosure.

We claim:
 1. A compound having the structure of Formula I-R or I-S or apharmaceutically acceptable isomer, enantiomer, racemate, salt, ester,prodrug, hydrate or solvate thereof:

wherein A is a 5-, 6- or 7-membered heterocyclyl having one, two orthree heteroatoms where each such heteroatom is independently selectedfrom O, N, and S, and where any ring atom of such heterocyclyl may beoptionally substituted with one or more of R₄; B is aryl, aralkyl,heterocyclyl, or heterocyclylalkyl; C is aryl, arylalkyl, heterocyclylor heterocyclylalkyl; Y₁ and Y₂ are both null, or one of Y₁ or Y₂ is—NH— or —O— and the other Y₁ or Y₂ is null; Z is —C(O)— or —S(O)₂—; eachR₁ is independently H or C₁₋₄ alkyl; R₂ is —OH, —O—R₈, —N(R₁)—SO₂—R₈,—NR₄₁R₄₂, —N(R₁)—(CR_(a)R_(b))_(m)—COOH,—N(R₁)—(CR_(a)R_(b))_(m)—CO—N(R₁)-heterocyclyl,—N(R₁)—(CR_(a)R_(b))_(m)—CO—N(R₁)(R₇), or —N(R₁)-heterocyclyl; each R₃and R₄ is independently H, halo, alkyl, alkyl substituted with R₃₁,alkoxy, haloalkyl, perhaloalkyl, haloalkoxy, perhaloalkoxy, aryl,heterocyclyl, —OH, —OR₈, —CN, —NO₂, —NR₁R₈, —C(O)R₈, —C(O)NR₁R₈,—NR₁C(O)R₈, —SR₈, —S(O)R₈, —S(O)₂R₈, —OS(O)₂R₈, —S(O)₂NR₁R₈,—NR₁S(O)₂R₈, —(CR_(a)R_(b))_(m)NR₁R₈,—(CR_(a)R_(b))_(m)O(CR_(a)R_(b))_(m)R₈,—(CR_(a)R_(b))_(m)NR₁(CR_(a)R_(b))_(m)R₈ or—(CR_(a)R_(b))_(m)NR₁(CR_(a)R_(b))_(m)COOH; or any two R₃ or R₄ groupson the same carbon atom taken together form oxo each R₃₁ isindependently H, halo, hydroxyl, —NR₄₁R₄₂, or alkoxy; each R₄₀ isindependently H or alkyl; each R₄₁ and R₄₂ is independently R₄₀ or—(CH₂)_(n)—COO—R₄₀, —C(O)—R₄₀, aryl, heteroaryl, or two taken togetherwith the N atom to which they are attached can form a 3- to 7-memberedheterocyclyl; W₁ is null or -L₁-(CR_(a)R_(b))_(m)-L₁-R₆; each L₁ isindependently, from the proximal to distal end of the structure ofFormula I-R or I-S, null, —C(O)O—, —S(O₂)—, —S—, —N(R₁)—C(O)—N(R₁)—,—N(R₁)—C(O)—O—, —C(O)— or —S(O₂)—NR₁—; each R_(a) and R_(b) isindependently H, alkyl, alkoxy, aryl, arylalkyl, heterocyclyl orheterocyclylalkyl, any of which alkyl, alkoxy, aryl, arylalkyl,heterocyclyl or heterocyclylalkyl may be optionally (singly or multiply)substituted with R₇, or —(CH₂)_(m)C(O)OR₄₀, —(CH₂)_(m)OR₄₀,—(CH₂)_(m)SR₄₀, —(CH₂)_(m)NR₄₁R₄₂, —(CH₂)_(m)C(O)NR₄₁R₄₂; or any twoR_(a) and R_(b) taken together with the carbon to which they areattached form a cycloalkyl or heterocyclyl; or R₁ and any one of R_(a)or R_(b) taken together form heterocyclyl; R₅ is R₇,—(CH₂)_(m)-L₂-(CH₂)_(m)—R₇, or -(-L₃-(CR_(a)R_(b))_(r)-)_(s)-L₃-R₇; R₆is H, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl,heterocycloalkyl, any of which may be optionally singly or multiplysubstituted with R₇ or —(CH₂)_(m)-L₂-(CH₂)_(m)—R₇; R₇ is H, halo, alkyl,haloalkyl, perhaloalkyl, alkoxy, —OH, —OR₈, —CN, —NR₁R₈,—(CR_(a)R_(b))_(m)O(CR_(a)R_(b))_(m)R₈, —NR₁(CR_(a)R_(b))_(m)R₈,—C(O)R₈, —NR₁(CR_(a)R_(b))_(m)COOH, —NR₁C(O)R₈, —C(O)NR₁R₈, —SR₈,—S(O)R₈, —S(O)₂R₈, —S(O)₂NR₁R₈, —NR₁S(O)₂R₈; or a ring moiety selectedfrom cycloalkyl, aryl, arylalkyl, heterocyclyl or heterocyclylalkyl,where such ring moiety is optionally singly or multiply substituted withhalo, —OH, —CN, alkyl, alkoxy, haloalkyl or perhaloalkyl; each R₈ isindependently H, alkyl, cycloalkyl or aryl; L₂ is independently, fromthe proximal to distal end of the structure of Formula I-R or I-S, null,—O—, —OC(O)—, —NR₁—, —C(O)NR₁—, —N(R₁)—C(O)—, —S(O₂)—, —C(O)— or—S(O₂)—N(R₁)—; each L₃ is independently null, —O—, or —N(R₁)— each m isindependently 0, 1, 2, 3, 4, 5 or 6; each n is independently 0 or 1 or2; p is 0, 1, 2 or 3; q is 0, 1, 2 or 3; each r is independently 2, 3,or 4; and each s is independently 1, 2, 3, or
 4. 2. The compound ofclaim 1 wherein Y₁ and Y₂ are null, Z is —C(O)— and A is a 5- or6-membered heteroaryl group.
 3. The compound of claim 2 wherein thecompound has the following structure:


4. The compound of claim 1 wherein Y₁ and Y₂ are null, Z is —C(O)— and Ais a 5- or 6-membered non-aromatic heterocycyl group.
 5. The compound ofclaim 4 wherein the compound has the following structure:


6. The compound of claim 1 wherein Y₁ and Y₂ are null, Z is —C(O)— and Cis aryl.
 7. The compound of claim 6 wherein the compound has thefollowing structure:


8. The compound of claim 1 wherein Y₁ and Y₂ are null, Z is —C(O)— and Cis heterocyclyl.
 9. The compound of claim 8 wherein the compound has thefollowing structure:


10. The compound of claim 1 wherein Y₁ and Y₂ are null, Z is —C(O)— andB is aryl or arylalkyl.
 11. The compound of claim 10 wherein thecompound has the following structure:


12. The compound of claim 1 wherein Y₁ and Y₂ are null, Z is —C(O)— andB is heterocyclyl or heterocyclylalkyl.
 13. The compound of claim 12wherein the compound has the following structure:


14. The compound of claim 1 wherein Y₁ and Y₂ are null, Z is —S(O)₂—.15. The compound of claim 14 wherein the compound has the followingstructure:


16. The compound of claim 1 wherein where Y₁ is null, Y₂ is —O— and Z is—C(O)—.
 17. The compound of claim 16 wherein the compound has thefollowing structure:


18. The compound of claim 1 wherein where Y₁ is NH, Y₂ is null and Z is—C(O)—.
 19. The compound of claim 18 wherein the compound has thefollowing structure:


20. A pharmaceutical composition comprising a compound of claim 1together with at least one pharmaceutically acceptable carrier, diluentor excipient.
 21. A pharmaceutical combination comprising the compoundof claim 1 and a second medicament.
 22. The pharmaceutical combinationof claim 21 wherein the second medicament is an agonist or modulator forglucagon receptor, GIP receptor, GLP-2 receptor, or PTH receptor, orglucagon-like peptide 1 (GLP-1) receptor.
 23. The pharmaceuticalcombination of claim 21 wherein the second medicament is exenatide,liraglutide, taspoglutide, albiglutide, or lixisenatide.
 24. Thepharmaceutical combination of claim 21 wherein the second medicament isa DPPIV inhibitor.
 25. A method of activation, potentiation, modulationor agonism of a glucagon-like peptide 1 receptor comprising contactingthe receptor with an effective amount of a compound of claim 1 or apharmaceutical composition of claim 20 or a pharmaceutical combinationof claim
 22. 26. A method of activation, potentiation, modulation oragonism of a glucagon-like peptide 1 (GLP-1) receptor in a subject inneed thereof, said method comprising administering to said subject acompound of claim 1 or a pharmaceutical composition of claim 20 or apharmaceutical combination of claim
 22. 27. A method of treatment of amalcondition in a patient for which activation, potentiation, modulationor agonism of a glucagon-like peptide 1 receptor is medically indicated,comprising administering an effective amount of the compound of claim 1to the patient at a frequency and for a duration of time sufficient toprovide a beneficial effect to the patient.
 28. The method of claim 27wherein the malcondition is type I diabetes, type II diabetes,gestational diabetes, obesity, excessive appetite, insufficient satietyor metabolic disorder.
 29. The method of claim 27 wherein themalcondition is type I diabetes or type II diabetes.